Secreted proteins

ABSTRACT

Various embodiments of the invention provide human secreted proteins (SECP) and polynucleotides which identify and encode SECP. Embodiments of the invention also provide expression vectors, host cells, antibodies, agonists, and antagonists. Other embodiments provide methods for diagnosing, treating, or preventing disorders associated with aberrant expression of SECP.

TECHNICAL FIELD

[0001] The invention relates to novel nucleic acids, secreted proteins encoded by these nucleic acids, and to the use of these nucleic acids and proteins in the diagnosis, treatment, and prevention of cell proliferative, autoimmune/inflammatory, cardiovascular, neurological, and developmental disorders. The invention also relates to the assessment of the effects of exogenous compounds on the expression of nucleic acids and secreted proteins.

BACKGROUND OF THE INVENTION

[0002] Protein transport and secretion are essential for cellular function. Protein transport is mediated by a signal peptide located at the amino terminus of the protein to be transported or secreted. The signal peptide is comprised of about ten to twenty hydrophobic amino acids which target the nascent protein from the ribosome to a particular membrane bound compartment such as the endoplasmic reticulum (ER). Proteins targeted to the ER may either proceed through the secretory pathway or remain in any of the secretory organelles such as the ER, Golgi apparatus, or lysosomes. Proteins that transit through the secretory pathway are either secreted into the extracellular space or retained in the plasma membrane. Proteins that are retained in the plasma membrane contain one or more transmembrane domains, each comprised of about 20 hydrophobic amino acid residues. Secreted proteins are generally synthesized as inactive precursors that are activated by post-translational processing events during transit through the secretory pathway. Such events include glycosylation, proteolysis, and removal of the signal peptide by a signal peptidase. Other events that may occur during protein transport include chaperone-dependent unfolding and folding of the nascent protein and interaction of the protein with a receptor or pore complex. Examples of secreted proteins with amino terminal signal peptides are discussed below and include proteins with important roles in cell-to-ell signaling. Such proteins include transmembrane receptors and cell surface markers, extracellular matrix molecules, cytokines, hormones, growth and differentiation factors, enzymes, neuropeptides, vasomediators, cell surface markers, and antigen recognition molecules. (Reviewed in Alberts, B. et al. (1994) Molecular Biology of The Cell, Garland Publishing, New York, N.Y., pp. 557-560, 582-592.)

[0003] Cell surface markers include cell surface antigens identified on leukocytic cells of the immune system. These antigens have been identified using systematic, monoclonal antibody (mAb)-based “shot gun” techniques. These techniques have resulted in the production of hundreds of mAbs directed against unknown cell surface leukocytic antigens. These antigens have been grouped into “clusters of differentiation” based on common immunocytochemical localization patterns in various differentiated and undifferentiated leukocytic cell types. Antigens in a given cluster are presumed to identify a single cell surface protein and are assigned a “cluster of differentiation” or “CD” designation. Some of the genes encoding proteins identified by CD antigens have been cloned and verified by standard molecular biology techniques. CD antigens have been characterized as both transmembrane proteins and cell surface proteins anchored to the plasma membrane via covalent attachment to fatty acid-containing glycolipids such as glycosylphosphatidylinositol (GPI). (Reviewed in Barclay, A. N. et al. (1995) The Leucocyte Antigen Facts Book, Academic Press, San Diego, Calif., pp. 17-20.)

[0004] Matrix proteins (MPs) are transmembrane and extracellular proteins which function in formation, growth, remodeling, and maintenance of tissues and as important mediators and regulators of the inflammatory response. The expression and balance of MPs may be perturbed by biochemical changes that result from congenital, epigenetic, or infectious diseases. In addition, MPs affect leukocyte migration, proliferation, differentiation, and activation in the immune response. MPs are frequently characterized by the presence of one or more domains which may include collagen-like domains, EGF-like domains, immunoglobulin-like domains, and fibronectin-like domains. In addition, MPs may be heavily glycosylated and may contain an Arginine-Glycine-Aspartate (RGD) tripeptide motif which may play a role in adhesive interactions. MPs include extracellular proteins such as fibronectin, collagen, galectin, vitronectin and its proteolytic derivative somatomedin B; and cell adhesion receptors such as cell adhesion molecules (CAMs), cadherins, and integrins. (Reviewed in Ayad, S. et al. (1994) The Extracellular Matrix Facts Book, Academic Press, San Diego, Calif., pp. 2-16; Ruoslahti, E. (1997) Kidney Int. 51:1413-1417; Sjaastad, M. D. and W. J. Nelson (1997) BioEssays 19:47-55.)

[0005] Mucins are highly glycosylated glycoproteins that are the major structural component of the mucus gel. The physiological functions of mucins are cytoprotection, mechanical protection, maintenance of viscosity in secretions, and cellular recognition. MUC6 is a human gastric mucin that is also found in gall bladder, pancreas, seminal vesicles, and female reproductive tract (Toribara, N. W. et al. (1997) J. Biol. Chem. 272:16398-16403). The MUC6 gene has been mapped to human chromosome 11 (Toribara, N. W. et al. (1993) J. Biol. Chem 268:5879-5885). Hemomucin is a novel Drosophila surface mucin that may be involved in the induction of antibacterial effector molecules (Theopold, U. et al. (1996) J. Biol. Chem. 217:12708-12715).

[0006] Tuftelins are one of four different enamel matrix proteins that have been identified so far. The other three known enamel matrix proteins are the amelogenins, enamelin and ameloblastin. Assembly of the enamel extracellular matrix from these component proteins is believed to be critical in producing a matrix competent to undergo mineral replacement (Paine, C. T. et al. (1998) Connect Tissue Res. 38:257-267). Tuftelin mRNA has been found to be expressed in human ameloblastoma tumor, a non-mineralized odontogenic tumor (Deutsch, D. et al. (1998) Connect. Tissue Res. 39:177-184).

[0007] Olfactomedin-related proteins are extracellular matrix, secreted glycoproteins with conserved C-terminal motifs. They are expressed in a wide variety of tissues and in a broad range of species, from Caenorhabditis elegans to Homo sapiens. Olfactomedin-related proteins comprise a gene family with at least 5 family members in humans. One of the five, TIGR/myocilin protein, is expressed in the eye and is associated with the pathogenesis of glaucoma (Kulkarni, N. H. et al. (2000) Genet. Res. 76:41-50). Research by Yokoyama, M. et al. (1996; DNA Res. 3:311-320) found a 135-amino acid protein, termed AMY, having 96% sequence identity with rat neuronal olfactomedin-releated ER localized protein in a neuroblastoma cell line cDNA library, suggesting an essential role for AMY in nerve tissue. Neuron-specific olfactomedin-related glycoproteins isolated from rat brain cDNA libraries show strong sequence similarity with olfactomedin. This similarity is suggestive of a matrix-related function of these glycoproteins in neurons and neurosecretory cells (Danielson, P. E. et al. (1994) J. Neurosci. Res. 38:468-478).

[0008] Mac-2 binding protein is a 90-kD serum protein (90K), a secreted glycoprotein isolated from both the human breast carcinoma cell line SK-BR-3, and human breast milk. It specifically binds to a human macrophage-associated lectin, Mac-2. Structurally, the mature protein is 567 amino acids in length and is proceeded by an 18-amino acid leader. There are 16 cysteines and seven potential N-linked glycosylation sites. The first 106 amino acids represent a domain very similar to an ancient protein superfamily defined by a macrophage scavenger receptor cysteine-rich domain (Koths, K. et al. (1993) J. Biol. Chem. 268:14245-14249). 90K is elevated in the serum of subpopulations of AIDS patients and is expressed at varying levels in primary tumor samples and tumor cell lines. Ullrich, A. et al. (1994; J. Biol. Chem. 269:18401-18407) have demonstrated that 90K stimulates host defense systems and can induce interleukin-2 secretion. This immune stimulation is proposed to be a result of oncogenic transformation, viral infection or pathogenic invasion (Ullrich et al., supra).

[0009] Semaphorins are a large group of axonal guidance molecules consisting of at least 30 different members and are found in vertebrates, invertebrates, and even certain viruses. All semaphorins contain the sema domain which is approximately 500 amino acids in length. Neuropilin, a semaphorin receptor, has been shown to promote neurite outgrowth in vitro. The extracellular region of neuropilins consists of three different domains: CUB, discoidin, and MAM domains. The CUB and the MAM motifs of neuropilin have been suggested to have roles in protein-protein interactions and are thought to be involved in the binding of semaphorins through the sema and the C-terminal domains (reviewed in Raper, J. A. (2000) Curr. Opin. Neurobiol. 10:88-94). Plexins are neuronal cell surface molecules that mediate cell adhesion via a homophilic binding mechanism in the presence of calcium ions. Plexins have been shown to be expressed in the receptors and neurons of particular sensory systems (Ohta, K. et al. (1995) Cell 14:1189-1199). There is evidence that suggests that some plexins function to control motor and CNS axon guidance in the developing nervous system. Plexins, which themselves contain complete semaphorin domains, may be both the ancestors of classical semaphorins and binding partners for semaphorins (Winberg, M. L. et al (1998) Cell 95:903-916).

[0010] Human pregnancy-specific beta 1-glycoprotein (PSG) is a family of closely related glycoproteins of molecular weights of 72 KDa, 64 KDa, 62 KDa, and 54 KDa. Together with the carcinoembryonic antigen, they comprise a subfamily within the immunoglobulin superfamily (Plouzek, C. A. and J. Y. Chou, (1991) Endocrinology 129:950-958) Different subpopulations of PSG have been found to be produced by the trophoblasts of the human placenta, and the amnionic and chorionic membranes (Plouzek, C. A. et al. (1993) Placenta 14:277-285).

[0011] Torsion dystonia is an autosomal dominant movement disorder consisting of involuntary muscular contractions. The disorder has been linked to a 3-base pair mutation in the DYT-1 gene, which encodes torsin A (Ozelius, L. J. et al. (1997) Nat. Genet. 17:4048). Torsin A bears significant homology to the Hsp100/Clp family of ATPase chaperones, which are conserved in humans, rats, mice, and C. elegans. Strong expression of DYT-1 in neuronal processes indicates a potential role for torsins in synaptic communication (Kustedjo, K. et al. (2000) J. Biol. Chen 275:27933-27939 and Konakova M. et al. (2001) Arch. Neurol. 58:921-927).

[0012] Autocrine motility factor (AMF) is one of the motility cytokines regulating tumor cell migration; therefore identification of the signaling pathway coupled with it has critical importance. Autocrine motility factor receptor (AMR) expression has been found to be associated with tumor progression in thymoma (Ohta Y. et al. (2000) Int. J. Oncol. 17:259-264). AMFR is a cell surface glycoprotein of molecular weight 78 KDa.

[0013] Hormones are secreted molecules that travel through the circulation and bind to specific receptors on the surface of, or within, target cells. Although they have diverse biochemical compositions and mechanisms of action, hormones can be grouped into two categories. One category includes small lipophilic hormones that diffuse through the plasma membrane of target cells, bind to cytosolic or nuclear receptors, and form a complex that alters gene expression. Examples of these molecules include retinoic acid, thyroxine, and the cholesterol-derived steroid hormones such as progesterone, estrogen, testosterone, cortisol, and aldosterone. The second category includes hydrophilic hormones that function by binding to cell surface receptors that transduce signals across the plasma membrane. Examples of such hormones include amino acid derivatives such as catecholamines (epinephrine, norepinephrine) and histamine, and peptide hormones such as glucagon, insulin, gastrin, secretin, cholecystokinin, adrenocorticotropic hormone, follicle stimulating hormone, luteinizing hormone, thyroid stimulating hormone, and vasopressin. (See, for example, Lodish et al. (1995) Molecular Cell Biology, Scientific American Books Inc., New York, N.Y., pp. 856-864.)

[0014] Pro-opiomelanocortin (POMC) is the precursor polypeptide of corticotropin (ACTH), a hormone synthesized by the anterior pituitary gland, which functions in the stimulation of the adrenal cortex. POMC is also the precursor polypeptide of the hormone beta-lipotropin (beta-LPH). Each hormone includes smaller peptides with distinct biological activities: alpha-melanotropin (alpha-MSH) and corticotropin-like intermediate lobe peptide (CLIP) are formed from ACTH; gamma-lipotropin (gamma-LPH) and beta-endorphin are peptide components of beta-LPH; while beta-MSH is contained within gamma-LPH. Adrenal insufficiency due to ACTH deficiency, resulting from a genetic mutation in exons 2 and 3 of POMC results in an endocrine disorder characterized by early-onset obesity, adrenal insufficiency, and red hair pigmentation (Chretien, M. et al. (1979) Can. J. Biochem. 57:1111-1121; Krude, H. et al. (1998) Nat. Genet. 19:155-157; Online Mendelian Inheritance in Man (OMIM) 176830).

[0015] Growth and differentiation factors are secreted proteins which function in intercellular communication. Some factors require oligomerization or association with membrane proteins for activity. Complex interactions among these factors and their receptors trigger intracellular signal transduction pathways that stimulate or inhibit cell division, cell differentiation, cell signaling, and cell motility. Most growth and differentiation factors act on cells in their local environment (paracrine signaling). There are three broad classes of growth and differentiation factors. The first class includes the large polypeptide growth factors such as epidermal growth factor, fibroblast growth factor, transforming growth factor, insulin-like growth factor, and platelet-derived growth factor. The second class includes the hematopoietic growth factors such as the colony stimulating factors (CSFs). Hematopoietic growth factors stimulate the proliferation and differentiation of blood cells such as B-lymphocytes, T-lymphocytes, erythrocytes, platelets, eosinophils, basophils, neutrophils, macrophages, and their stem cell precursors. The third class includes small peptide factors such as bombesin, vasopressin, oxytocin, endothelin, transferrin, angiotensin II, vasoactive intestinal peptide, and bradykinin, which function as hormones to regulate cellular functions other than proliferation.

[0016] Growth and differentiation factors play critical roles in neoplastic transformation of cells in vitro and in tumor progression in vivo. Inappropriate expression of growth factors by tumor cells may contribute to vascularization and metastasis of tumors. During hematopoiesis, growth factor misregulation can result in anemias, leukemias, and lymphomas. Certain growth factors such as interferon are cytotoxic to tumor cells both in vivo and in vitro. Moreover, some growth factors and growth factor receptors are related both structurally and functionally to oncoproteins. In addition, growth factors affect transcriptional regulation of both proto-oncogenes and oncosuppressor genes. (Reviewed in Pimentel, E. (1994) Handbook of Growth Factors, CRC Press, Ann Arbor, Mich., pp. 1-9.)

[0017] The Slit protein, first identified in Drosophila, is critical in central nervous system midline formation and potentially in nervous tissue histogenesis and axonal pathfinding. Itoh et al. (1998; Brain Res. Mol. Brain Res. 62:175-186) have identified mammalian homologues of the slit gene (human Slit-1, Slit-2, Slit-3 and rat Slit-1). The encoded proteins are putative secreted proteins containing EGF-like motifs and leucine-rich repeats, both of which are conserved protein-protein interaction domains. Slit-1, -2, and -3 mRNAs are expressed in the brain, spinal cord, and thyroid, respectively (Itoh et al., supra). The Slit family of proteins are indicated to be functional ligands of glypican-1 in nervous tissue and it is suggested that their interactions may be critical in certain stages during central nervous system histogenesis (Liang, Y. et al. (1999) J. Biol. Chem. 274:17885-17892).

[0018] Neuropeptides and vasomediators (NP/VM) comprise a large family of endogenous signaling molecules. Included in this family are neuropeptides and neuropeptide hormones such as bombesin, neuropeptide Y, neurotensin, neuromedin N, melanocortins, opioids, galanin, somatostatin, tachykinins, urotensin II and related peptides involved in smooth muscle stimulation, vasopressin, vasoactive intestinal peptide, and circulatory system-borne signaling molecules such as angiotensin, complement, calcitonin, endothelins, formyl-methionyl peptides, glucagon, cholecystokinin and gastrin. NP/VMs can transduce signals directly, modulate the activity or release of other neurotransmitters and hormones, and act as catalytic enzymes in cascades. The effects of NP/VMs range from extremely brief to long-lasting. (Reviewed in Martin, C. R. et al. (1985) Endocrine Physiology, Oxford University Press, New York, N.Y., pp. 57-62.)

[0019] NP/VMs are involved in numerous neurological and cardiovascular disorders. For example, neuropeptide Y is involved in hypertension, congestive heart failure, affective disorders, and appetite regulation. Somatostatin inhibits secretion of growth hormone and prolactin in the anterior pituitary, as well as inhibiting secretion in intestine, pancreatic acinar cells, and pancreatic beta-cells. A reduction in somatostatin levels has been reported in Alzheimer's disease and Parkinson's disease. Vasopressin acts in the kidney to increase water and sodium absorption, and in higher concentrations stimulates contraction of vascular smooth muscle, platelet activation, and glycogen breakdown in the liver. Vasopressin and its analogues are used clinically to treat diabetes insipidus. Endothelin and angiotensin are involved in hypertension, and drugs, such as captopril, which reduce plasma levels of angiotensin, are used to reduce blood pressure (Watson, S. and S. Arkinstall (1994) The G-protein Linked Receptor Facts Book, Academic Press, San Diego Calif., pp. 194; 252; 284; 55; 111).

[0020] Neuropeptides have also been shown to have roles in nociception (pain). Vasoactive intestinal peptide appears to play an important role in chronic neuropathic pain. Nociceptin, an endogenous ligand for for the opioid receptor-like 1 receptor, is thought to have a predominantly anti-nociceptive effect, and has been shown to have analgesic properties in different animal models of tonic or chronic pain (Dickinson, T. and S. M. Fleetwood-Walker (1998) Trends Pharmacol. Sci. 19:346-348).

[0021] Other proteins that contain signal peptides include secreted proteins with enzymatic activity. Such activity includes, for example, oxidoreductase/dehydrogenase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, or ligase activity. For example, matrix metalloproteinases are secreted hydrolytic enzymes that degrade the extracellular matrix and thus play an important role in tumor metastasis, tissue morphogenesis, and arthritis (Reponen, P. et al. (1995) Dev. Dyn. 202:388-396; Firestein, G. S. (1992) Curr. Opin. Rheumatol. 4:348-354; Ray, J. M. and W. G. Stetler-Stevenson (1994) Eur. Respir. J. 7:2062-2072; and Mignatti, P. and D. B. Rifkin (1993) Physiol. Rev. 73:161-195). Additional examples are the acetyl-CoA synthetases which activate acetate for use in lipid synthesis or energy generation (Luong, A. et al. (2000) J. Biol. Chem. 275:26458-26466). The result of acetyl-CoA synthetase activity is the formation of acetyl-CoA from acetate and CoA. Acetyl-CoA synthetases share a region of sequence similarity identified as the AMP-binding domain signature. Acetyl-CoA synthetase has been shown to be associated with hypertension (Toh, H. (1991) Protein Seq. Data Anal. 4:111-117; and Iwai, N. et al. (1994) Hypertension 23:375-380).

[0022] A number of isomerases catalyze steps in protein folding, phototransduction, and various anabolic and catabolic pathways. One class of isomerases is known as peptidyl-prolyl cis-trans isomerases (PPIases). PPIases catalyze the cis to trans isomerization of certain proline imidic bonds in proteins. Two families of PPIases are the FK506 binding proteins (FKBPs), and cyelophilins (CyPs). FKBPs bind the potent immunosuppressants FK506 and rapamycin, thereby inhibiting signaling pathways in T-cells. Specifically, the PPIase activity of FKBPs is inhibited by binding of FK506 or rapamycin. There are five members of the FKBP family which are named according to their calculated molecular masses (FKBP12, FKBP13, FKBP25, FKBP52, and FKBP65), and localized to different regions of the cell where they associate with different protein complexes (Coss, M. et al. (1995) J. Biol. Chem. 270:29336-29341; Schreiber, S. L. (1991) Science 251:283-287).

[0023] The peptidyl-prolyl isomerase activity of CyP may be part of the signaling pathway that leads to T-cell activation. CyP isomerase activity is associated with protein folding and protein trafficking, and may also be involved in assembly/disassembly of protein complexes and regulation of protein activity. For example, in Drosophila, the CyP NinaA is required for correct localization of rhodopsins, while a mammalian CyP (Cyp40) is part of the Hsp90/Hsc70 complex that binds steroid receptors. The mammalian CypA has been shown to bind the gag protein from human immunodeficiency virus 1 (HIV-1), an interaction that can be inhibited by cyclosporin. Since cyclosporin has potent anti-HIV-1 activity, CypA may play an essential function in HIV-1 replication. Finally, Cyp40 has been shown to bind and inactivate the transcription factor c-Myb, an effect that is reversed by cyclosporin. This effect implicates CyPs in the regulation of transcription, transformation, and differentiation (Bergsma, D. J. et al (1991) J. Biol. Chem. 266:23204-23214; Hunter, T. (1998) Cell 92:141-143; and Leverson, J. D. and S. A. Ness, (1998) Mol. Cell. 1:203-211).

[0024] Gamma-carboxyglutamic acid (Gla) proteins rich in proline (PRGPs) are members of a family of vitamin K-dependent single-pass integral membrane proteins. These proteins are characterized by an extracellular amino terminal domain of approximately 45 amino acids rich in Gla. The intracellular carboxyl terminal region contains one or two copies of the sequence PPXY, a motif present in a variety of proteins involved in such diverse cellular functions as signal transduction, cell cycle progression, and protein turnover (Kulman, J. D. et al. (2001) Proc. Natl. Acad. Sci. USA 98:1370-1375). The process of post-translational modification of glutamic residues to form Gla is Vitamin K-dependent carboxylation. Proteins which contain Gla include plasma proteins involved in blood coagulation. These proteins are prothrombin, proteins C, S, and Z, and coagulation factors VII, IX, and X. Osteocalcin (bone-Gla protein, BGP) and matrix Gla-protein (MGP) also contain Gla (Friedman, P. A. and C. T. Przysiecki (1987) Int. J. Biochem. 19:1-7; Vermeer, C. (1990) Biochem. J. 266:625-636).

[0025] Immunoglobulins

[0026] Antigen recognition molecules are key players in the sophisticated and complex immune systems which all vertebrates have developed to provide protection from viral, bacterial, fungal, and parasitic infections. A key feature of the immune system is its ability to distinguish foreign molecules, or antigens, from “self” molecules. This ability is mediated primarily by secreted and transmembrane proteins expressed by leukocytes (white blood cells) such as lymphocytes, granulocytes, and monocytes. Most of these proteins belong to the immunoglobulin (Ig) superfamily, members of which contain one or more repeats of a conserved structural domain. This Ig domain is comprised of antiparallel β sheets joined by a disulfide bond in an arrangement called the Ig fold. The criteria for a protein to be a member of the Ig superfamily is to have one or more Ig domains, which are regions of 70-110 amino acid residues in length homologous to either Ig variable-like (V) or Ig constant-like (C) domains. Members of the Ig superfamily include antibodies (Ab), T cell receptors (TCRs), class I and II major histocompatibility (MHC) proteins and immune cell-specific surface markers such as the “cluster of differentiation” or CD antigens, CD2, CD3, CD4, CD8, poly-Ig receptors, Fc receptors, neural cell-adhesion molecule (NCAM) and platelet-derived growth factor receptor (PDGFR).

[0027] Ig domains (V and C) are regions of conserved amino acid residues that give a polypeptide a globular tertiary structure called an immunoglobulin (or antibody) fold, which consists of two approximately parallel layers of β-sheets. Conserved cysteine residues form an intrachain disulfide-bonded loop, 55-75 amino acid residues in length, which connects the two layers of β-sheets. Each β-sheet has three or four anti-parallel β-strands of 5-10 amino acid residues. Hydrophobic and hydrophilic interactions of amino acid residues within the β-strands stabilize the Ig fold (hydrophobic on inward facing amino acid residues and hydrophilic on the amino acid residues in the outward facing portion of the strands). A V domain consists of a longer polypeptide than a C domain, with an additional pair of β-strands in the Ig fold.

[0028] A consistent feature of Ig superfamily genes is that each sequence of an Ig domain is encoded by a single exon. It is possible that the superfamily evolved from a gene coding for a single Ig domain involved in mediating cell-cell interactions. New members of the superfamily then arose by exon and gene duplications. Modern Ig superfamily proteins contain different numbers of V and/or C domains. Another evolutionary feature of this superfamily is the ability to undergo DNA rearrangements, a unique feature retained by the antigen receptor members of the family.

[0029] Many members of the Ig superfamily are integral plasma membrane proteins with extracellular Ig domains. The hydrophobic amino acid residues of their transmembrane domains and their cytoplasmic tails are very diverse, with little or no homology among Ig family members or to known signal-transducing structures. There are exceptions to this general superfamily description. For example, the cytoplasmic tail of PDGFR has tyrosine kinase activity. In addition Thy-1 is a glycoprotein found on thymocytes and T cells. This protein has no cytoplasmic tail, but is instead attached to the plasma membrane by a covalent glycophosphatidylinositol linkage.

[0030] Another common feature of many Ig superfamily proteins is the interactions between Ig domains which are essential for the function of these molecules. Interactions between Ig domains of a multimeric protein can be either homophilic or heterophilic (i.e., between the same or different Ig domains). Antibodies are multimeric proteins which have both homophilic and heterophilic interactions between Ig domains. Pairing of constant regions of heavy chains forms the Fc region of an antibody and pairing of variable regions of light and heavy chains form the antigen binding site of an antibody. Heterophilic interactions also occur between Ig domains of different molecules. These interactions provide adhesion between cells for significant cell-cell interactions in the immune system and in the developing and mature nervous system. (Reviewed in Abbas, A. K. et al. (1991) Cellular and Molecular Immunology, W. B. Saunders Company, Philadelphia, Pa., pp. 142-145.)

[0031] Antibodies

[0032] MHC proteins are cell surface markers that bind to and present foreign antigens to T cells. MRC molecules are classified as either class I or class II. Class I MHC molecules (MHC I) are expressed on the surface of almost all cells and are involved in the presentation of antigen to cytotoxic T cells. For example, a cell infected with virus will degrade intracellular viral proteins and express the protein fragments bound to MHC I molecules on the cell surface. The MHC I/antigen complex is recognized by cytotoxic T-cells which destroy the infected cell and the virus within. Class II MHC molecules are expressed primarily on specialized antigen-presenting cells of the immune system, such as B-cells and macrophages. These cells ingest foreign proteins from the extracellular fluid and express MHC II/antigen complex on the cell surface. This complex activates helper T-cells, which then secrete cytokines and other factors that stimulate the immune response. MHC molecules also play an important role in organ rejection following transplantation. Rejection occurs when the recipient's T-cells respond to foreign MHC molecules on the transplanted organ in the same way as to self MHC molecules bound to foreign antigen. (Reviewed in Alberts et al., supra, pp. 1229-1246.)

[0033] Antibodies are multimeric members of the Ig superfamily which are either expressed on the surface of B-cells or secreted by B-cells into the circulation. Antibodies bind and neutralize foreign antigens in the blood and other extracellular fluids. The prototypical antibody is a tetramer consisting of two identical heavy polypeptide chains (H-chains) and two identical light polypeptide chains (L-chains) interlinked by disulfide bonds. This arrangement confers the characteristic Y-shape to antibody molecules. Antibodies are classified based on their H-chain composition. The five antibody classes, IgA, IgD, IgE, IgG and IgM, are defined by the α, δ, ε, γ, and μ H-chain types. There are two types of L-chains, κ and λ, either of which may associate as a pair with any H-chain pair. IgG, the most common class of antibody found in the circulation, is tetrameric, while the other classes of antibodies are generally variants or multimers of this basic structure.

[0034] H-chains and L-chains each contain an N-terminal variable region and a C-terminal constant region. The constant region consists of about 110 amino acids in L-chains and about 330 or 440 amino acids in H-chains. The amino acid sequence of the constant region is nearly identical among H- or L-chains of a particular class. The variable region consists of about 110 amino acids in both H- and L-chains. However, the amino acid sequence of the variable region differs among H- or L-chains of a particular class. Within each H- or L-chain variable region are three hypervariable regions of extensive sequence diversity, each consisting of about 5 to 10 amino acids. In the antibody molecule, the H- and L-chain hypervariable regions come together to form the antigen recognition site. (Reviewed in Alberts et al. supra, pp. 1206-1213; 1216-1217.)

[0035] Both H-chains and L-chains contain the repeated Ig domains of members of the Ig superfamily. For example, a typical H-chain contains four Ig domains, three of which occur within the constant region and one of which occurs within the variable region and contributes to the formation of the antigen recognition site. Likewise, a typical L-chain contains two Ig domains, one of which occurs within the constant region and one of which occurs within the variable region.

[0036] The immune system is capable of recognizing and responding to any foreign molecule that enters the body. Therefore, the immune system must be armed with a full repertoire of antibodies against all potential antigens. Such antibody diversity is generated by somatic rearrangement of gene segments encoding variable and constant regions. These gene segments are joined together by site-specific recombination which occurs between highly conserved DNA sequences that flank each gene segment. Because there are hundreds of different gene segments, millions of unique genes can be generated combinatorially. In addition, imprecise joining of these segments and an unusually high rate of somatic mutation within these segments further contribute to the generation of a diverse antibody population.

[0037] Expression Profiling

[0038] Microarrays are analytical tools used in bioanalysis. A microarray has a plurality of molecules spatially distributed over, and stably associated with, the surface of a solid support. Microarrays of polypeptides, polynucleotides, and/or antibodies have been developed and find use in a variety of applications, such as gene sequencing, monitoring gene expression, gene mapping, bacterial identification, drug discovery, and combinatorial chemistry.

[0039] One area in particular in which microarrays find use is in gene expression analysis. Array technology can provide a simple way to explore the expression of a single polymorphic gene or the expression profile of a large number of related or unrelated genes. When the expression of a single gene is examined, arrays are employed to detect the expression of a specific gene or its variants. When an expression profile is examined, arrays provide a platform for identifying genes that are tissue specific, are affected by a substance being tested in a toxicology assay, are part of a signaling cascade, carry out housekeeping functions, or are specifically related to a particular genetic predisposition, condition, disease, or disorder.

[0040] The potential application of gene expression profiling is particularly relevant to improving the diagnosis, prognosis, and treatment of cancers, including colon cancer.

[0041] Colon Cancer

[0042] While soft tissue sarcomas are relatively rare, more than 50% of new patients diagnosed with the disease will die from it. The molecular pathways leading to the development of sarcomas are relatively unknown, due to the rarity of the disease and variation in pathology. Colon cancer evolves through a multi-step process whereby pre-malignant colonocytes undergo a relatively defined sequence of events leading to tumor formation. Several factors participate in the process of tumor progression and malignant transformation including genetic factors, mutations, and selection.

[0043] To understand the nature of gene alterations in colorectal cancer, a number of studies have focused on the inherited syndromes. The first, Familial Adenomatous Polyposis (PAP), is caused by mutations in the Adenomatous Polyposis Coli gene (APC), resulting in truncated or inactive forms of the protein. This tumor suppressor gene has been mapped to chromosome 5q. The second known inherited syndrome is hereditary nonpolyposis colorectal cancer (HNPCC), which is caused by mutations in mismatch repair genes.

[0044] Although hereditary colon cancer syndromes occur in a small percentage of the population, and most colorectal cancers are considered sporadic, knowledge from studies of the hereditary syndromes can be applied broadly. For instance, somatic mutations in APC occur in at least 80% of sporadic colon tumors. APC mutations are thought to be the initiating event in disease progression. Other mutations occur subsequently. Approximately 50% of colorectal cancers contain activating mutations in ras, while 85% contain inactivating mutations in p53. Changes in all of these genes lead to gene expression changes in colon cancer. Less is understood about downstream targets of these mutations and the role they may play in cancer development and progression.

[0045] There is a need in the art for new compositions, including nucleic acids and proteins, for the diagnosis, prevention, and treatment of cell proliferative, autoimmune/inflammatory, cardiovascular, neurological, and developmental disorders.

SUMMARY OF THE INVENTION

[0046] Various embodiments of the invention provide purified polypeptides, secreted proteins, referred to collectively as “SECP” and individually as “SECP-1,” “SECP-2,” “SECP-3,” “SECP-4,” “SECP-5,” “SECP-6,” “SECP-7,” “SECP-8,” “SECP-9,” “SECP-10,” “SECP-11,” “SECP-12,” “SECP-13,” “SECP-14,” “SECP-15,” “SECP-16,” “SECP-17,” “SECP-18,” “SECP-19,” “SECP-20,” “SECP-21,” “SECP-22,” “SECP-23,” “SECP-24,” “SECP-25,” “SECP-26,” “SECP-27,” “SECP-28,” “SECP-29,” “SECP-30,” and “SECP-31,” and methods for using these proteins and their encoding polynucleotides for the detection, diagnosis, and treatment of diseases and medical conditions. Embodiments also provide methods for utilizing the purified secreted proteins and/or their encoding polynucleotides for facilitating the drug discovery process, including determination of efficacy, dosage, toxicity, and pharmacology. Related embodiments provide methods for utilizing the purified secreted proteins and/or their encoding polynucleotides for investigating the pathogenesis of diseases and medical conditions.

[0047] An embodiment provides an isolated polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31. Another embodiment provides an isolated polypeptide comprising an amino acid sequence of SEQ ID NO:1-31.

[0048] Still another embodiment provides an isolated polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31. In another embodiment, the polynucleotide encodes a polypeptide selected from the group consisting of SEQ ID NO:1-31. In an alternative embodiment, the polynucleotide is selected from the group consisting of SEQ ID NO:32-62.

[0049] Still another embodiment provides a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31. Another embodiment provides a cell transformed with the recombinant polynucleotide. Yet another embodiment provides a transgenic organism comprising the recombinant polynucleotide.

[0050] Another embodiment provides a method for producing a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-31. The method comprises a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding the polypeptide, and b) recovering the polypeptide so expressed.

[0051] Yet another embodiment provides an isolated antibody which specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31.

[0052] Still yet another embodiment provides an isolated polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). In other embodiments, the polynucleotide can comprise at least about 20, 30, 40, 60, 80, or 100 contiguous nucleotides.

[0053] Yet another embodiment provides a method for detecting a target polynucleotide in a sample, said target polynucleotide being selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). The method comprises a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex. In a related embodiment, the method can include detecting the amount of the hybridization complex. In still other embodiments, the probe can comprise at least about 20, 30, 40, 60, 80, or 100 contiguous nucleotides.

[0054] Still yet another embodiment provides a method for detecting a target polynucleotide in a sample, said target polynucleotide being selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). The method comprises a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof. In a related embodiment, the method can include detecting the amount of the amplified target polynucleotide or fragment thereof.

[0055] Another embodiment provides a composition comprising an effective amount of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and a pharmaceutically acceptable excipient. In one embodiment, the composition can comprise an amino acid sequence selected from the group consisting of SEQ ID NO:1-31. Other embodiments provide a method of treating a disease or condition associated with decreased or abnormal expression of functional SECP, comprising administering to a patient in need of such treatment the composition.

[0056] Yet another embodiment provides a method for screening a compound for effectiveness as an agonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting agonist activity in the sample. Another embodiment provides a composition comprising an agonist compound identified by the method and a pharmaceutically acceptable excipient. Yet another embodiment provides a method of treating a disease or condition associated with decreased expression of functional SECP, comprising administering to a patient in need of such treatment the composition.

[0057] Still yet another embodiment provides a method for screening a compound for effectiveness as an antagonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting antagonist activity in the sample. Another embodiment provides a composition comprising an antagonist compound identified by the method and a pharmaceutically acceptable excipient. Yet another embodiment provides a method of treating a disease or condition associated with overexpression of functional SECP, comprising administering to a patient in need of such treatment the composition.

[0058] Another embodiment provides a method of screening for a compound that specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31. The method comprises a) combining the polypeptide with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide to the test compound, thereby identifying a compound that specifically binds to the polypeptide.

[0059] Yet another embodiment provides a method of screening for a compound that modulates the activity of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31. The method comprises a) combining the polypeptide with at least one test compound under conditions permissive for the activity of the polypeptide, b) assessing the activity of the polypeptide in the presence of the test compound, and c) comparing the activity of the polypeptide in the presence of the test compound with the activity of the polypeptide in the absence of the test compound, wherein a change in the activity of the polypeptide in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide.

[0060] Still yet another embodiment provides a method for screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62, the method comprising a) exposing a sample comprising the target polynucleotide to a compound, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound.

[0061] Another embodiment provides a method for assessing toxicity of a test compound, said method comprising a) treating a biological sample containing nucleic acids with the test compound; b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62, iii) a polynucleotide having a sequence complementary to i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Hybridization occurs under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62, iii) a polynucleotide complementary to the polynucleotide of i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Alternatively, the target polynucleotide can comprise a fragment of a polynucleotide selected from the group consisting of i)-v) above; c) quantifying the amount of hybridization complex; and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.

BRIEF DESCRIPTION OF THE TABLES

[0062] Table 1 summarizes the nomenclature for full length polynucleotide and polypeptide embodiments of the invention.

[0063] Table 2 shows the GenBank identification number and annotation of the nearest GenBank homolog for polypeptide embodiments of the invention. The probability scores for the matches between each polypeptide and its homolog(s) are also shown.

[0064] Table 3 shows structural features of polypeptide embodiments, including predicted motifs and domains, along with the methods, algorithms, and searchable databases used for analysis of the polypeptides.

[0065] Table 4 lists the cDNA and/or genomic DNA fragments which were used to assemble polynucleotide embodiments, along with selected fragments of the polynucleotides.

[0066] Table 5 shows representative cDNA libraries for polynucleotide embodiments.

[0067] Table 6 provides an appendix which describes the tissues and vectors used for construction of the cDNA libraries shown in Table 5.

[0068] Table 7 shows the tools, programs, and algorithms used to analyze polynucleotides and polypeptides, along with applicable descriptions, references, and threshold parameters.

DESCRIPTION OF THE INVENTION

[0069] Before the present proteins, nucleic acids, and methods are described, it is understood that embodiments of the invention are not limited to the particular machines, instruments, materials, and methods described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention.

[0070] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a host cell” includes a plurality of such host cells, and a reference to “an antibody” is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.

[0071] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any machines, materials, and methods similar or equivalent to those described herein can be used to practice or test the present invention, the preferred machines, materials and methods are now described. All publications mentioned herein are cited for the purpose of describing and disclosing the cell lines, protocols, reagents and vectors which are reported in the publications and which might be used in connection with various embodiments of the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

Definitions

[0072] “SECP” refers to the amino acid sequences of substantially purified SECP obtained from any species, particularly a mammalian species, including bovine, ovine, porcine, murine, equine, and human, and from any source, whether natural, synthetic, semi-synthetic, or recombinant.

[0073] The term “agonist” refers to a molecule which intensifies or mimics the biological activity of SECP. Agonists may include proteins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of SECP either by directly interacting with SECP or by acting on components of the biological pathway in which SECP participates.

[0074] An “allelic variant” is an alternative form of the gene encoding SECP. Allelic variants may result from at least one mutation in the nucleic acid sequence and may result in altered mRNAs or in polypeptides whose structure or function may or may not be altered. A gene may have none, one, or many allelic variants of its naturally occurring form. Common mutational changes which give rise to allelic variants are generally ascribed to natural deletions, additions, or substitutions of nucleotides. Each of these types of changes may occur alone, or in combination with the others, one or more times in a given sequence.

[0075] “Altered” nucleic acid sequences encoding SECP include those sequences with deletions, insertions, or substitutions of different nucleotides, resulting in a polypeptide the same as SECP or a polypeptide with at least one functional characteristic of SECP. Included within this definition are polymorphisms which may or may not be readily detectable using a particular oligonucleotide probe of the polynucleotide encoding SECP, and improper or unexpected hybridization to allelic variants, with a locus other than the normal chromosomal locus for the polynucleotide encoding SECP. The encoded protein may also be “altered,” and may contain deletions, insertions, or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent SECP. Deliberate amino acid substitutions may be made on the basis of one or more similarities in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues, as long as the biological or immunological activity of SECP is retained. For example, negatively charged amino acids may include aspartic acid and glutamic acid, and positively charged amino acids may include lysine and arginine. Amino acids with uncharged polar side chains having similar hydrophilicity values may include: asparagine and glutamine; and serine and threonine. Amino acids with uncharged side chains having similar hydrophilicity values may include: leucine, isoleucine, and valine; glycine and alanine; and phenylalanine and tyrosine.

[0076] The terms “amino acid” and “amino acid sequence” can refer to an oligopeptide, a peptide, a polypeptide, or a protein sequence, or a fragment of any of these, and to naturally occurring or synthetic molecules. Where “amino acid sequence” is recited to refer to a sequence of a naturally occurring protein molecule, “amino acid sequence” and like terms are not meant to limit the amino acid sequence to the complete native amino acid sequence associated with the recited protein molecule.

[0077] “Amplification” relates to the production of additional copies of a nucleic acid. Amplification may be carried out using polymerase chain reaction (PCR) technologies or other nucleic acid amplification technologies well known in the art.

[0078] The term “antagonist” refers to a molecule which inhibits or attenuates the biological activity of SECP. Antagonists may include proteins such as antibodies, anticalins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of SECP either by directly interacting with SECP or by acting on components of the biological pathway in which SECP participates.

[0079] The term “antibody” refers to intact immunoglobulin molecules as well as to fragments thereof, such as Fab, F(ab′)₂, and Fv fragments, which are capable of binding an epitopic determinant. Antibodies that bind SECP polypeptides can be prepared using intact polypeptides or using fragments containing small peptides of interest as the immunizing antigen. The polypeptide or oligopeptide used to immunize an animal (e.g., a mouse, a rat, or a rabbit) can be derived from the translation of RNA, or synthesized chemically, and can be conjugated to a carrier protein if desired. Commonly used carriers that are chemically coupled to peptides include bovine serum albumin, thyroglobulin, and keyhole limpet hemocyanin (KLH). The coupled peptide is then used to immunize the animal.

[0080] The term “antigenic determinant” refers to that region of a molecule (i.e., an epitope) that makes contact with a particular antibody. When a protein or a fragment of a protein is used to immunize a host animal, numerous regions of the protein may induce the production of antibodies which bind specifically to antigenic determinants (particular regions or three-dimensional structures on the protein). An antigenic determinant may compete with the intact antigen (i.e., the immunogen used to elicit the immune response) for binding to an antibody.

[0081] The term “aptamer” refers to a nucleic acid or oligonucleotide molecule that binds to a specific molecular target. Aptamers are derived from an in vitro evolutionary process (e.g., SELEX (Systematic Evolution of Ligands by EXponential Enrichment), described in U.S. Pat. No. 5,270,163), which selects for target-specific aptamer sequences from large combinatorial libraries. Aptamer compositions may be double-stranded or single-stranded, and may include deoxyribonucleotides, ribonucleotides, nucleotide derivatives, or other nucleotide-like molecules. The nucleotide components of an aptamer may have modified sugar groups (e.g., the 2′-OH group of a ribonucleotide may be replaced by 2′-F or 2′-NH₂), which may improve a desired property, e.g., resistance to nucleases or longer lifetime in blood. Aptamers may be conjugated to other molecules, e.g., a high molecular weight carrier to slow clearance of the aptamer from the circulatory system. Aptamers may be specifically cross-linked to their cognate ligands, e.g., by photo-activation of a cross-linker (Brody, E. N. and L. Gold (2000) J. Biotechnol. 74:5-13).

[0082] The term “intramer” refers to an aptamer which is expressed in vivo. For example, a vaccinia virus-based RNA expression system has been used to express specific RNA aptamers at high levels in the cytoplasm of leukocytes (Blind, M. et al. (1999) Proc. Natl. Acad. Sci. USA 96:3606-3610).

[0083] The term “spiegelmer” refers to an aptamer which includes L-DNA, L-RNA, or other left-handed nucleotide derivatives or nucleotide-like molecules. Aptamers containing left-handed nucleotides are resistant to degradation by naturally occurring enzymes, which normally act on substrates containing right-handed nucleotides.

[0084] The term “antisense” refers to any composition capable of base-pairing with the “sense” (coding) strand of a polynucleotide having a specific nucleic acid sequence. Antisense compositions may include DNA; RNA; peptide nucleic acid (PNA); oligonucleotides having modified backbone linkages such as phosphorothioates, methylphosphonates, or benzylphosphonates; oligonucleotides having modified sugar groups such as 2′-methoxyethyl sugars or 2′-methoxyethoxy sugars; or oligonucleotides having modified bases such as 5-methyl cytosine, 2′-deoxyuracil, or 7-deaza-2′-deoxyguanosine. Antisense molecules may be produced by any method including chemical synthesis or transcription. Once introduced into a cell, the complementary antisense molecule base-pairs with a naturally occurring nucleic acid sequence produced by the cell to form duplexes which block either transcription or translation. The designation “negative” or “minus” can refer to the antisense strand, and the designation “positive” or “plus” can refer to the sense strand of a reference DNA molecule.

[0085] The term “biologically active” refers to a protein having structural, regulatory, or biochemical functions of a naturally occurring molecule. Likewise, “immunologically active” or “immunogenic” refers to the capability of the natural, recombinant, or synthetic SECP, or of any oligopeptide thereof, to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.

[0086] “Complementary” describes the relationship between two single-stranded nucleic acid sequences that anneal by base-pairing. For example, 5′-AGT-3′ pairs with its complement, 3′-TCA-5′.

[0087] A “composition comprising a given polynucleotide” and a “composition comprising a given polypeptide” can refer to any composition containing the given polynucleotide or polypeptide. The composition may comprise a dry formulation or an aqueous solution. Compositions comprising polynucleotides encoding SECP or fragments of SECP may be employed as hybridization probes. The probes may be stored in freeze-dried form and may be associated with a stabilizing agent such as a carbohydrate. In hybridizations, the probe may be deployed in an aqueous solution containing salts (e.g., NaCl), detergents (e.g., sodium dodecyl sulfate; SDS), and other components (e.g., Denhardt's solution, dry milk, salmon sperm DNA, etc.).

[0088] “Consensus sequence” refers to a nucleic acid sequence which has been subjected to repeated DNA sequence analysis to resolve uncalled bases, extended using the XL-PCR kit (Applied Biosystems, Foster City Calif.) in the 5′ and/or the 3′ direction, and resequenced, or which has been assembled from one or more overlapping cDNA, EST, or genomic DNA fragments using a computer program for fragment assembly, such as the GEL VIEW fragment assembly system (GCG, Madison Wis.) or Phrap (University of Washington, Seattle Wash.). Some sequences have been both extended and assembled to produce the consensus sequence.

[0089] “Conservative amino acid substitutions” are those substitutions that are predicted to least interfere with the properties of the original protein, i.e., the structure and especially the function of the protein is conserved and not significantly changed by such substitutions. The table below shows amino acids which may be substituted for an original amino acid in a protein and which are regarded as conservative amino acid substitutions. Original Residue Conservative Substitution Ala Gly, Ser Arg His, Lys Asn Asp, Gln, His Asp Asn, Glu Cys Ala, Ser Gln Asn, Glu, His Glu Asp, Gln, His Gly Ala His Asn, Arg, Gln, Glu Ile Leu, Val Leu Ile, Val Lys Arg, Gln, Glu Met Leu, Ile Phe His, Met, Leu, Trp, Tyr Ser Cys, Thr Thr Ser, Val Trp Phe, Tyr Tyr His, Phe, Trp Val Ile, Leu, Thr

[0090] Conservative amino acid substitutions generally maintain (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a beta sheet or alpha helical conformation, (b) the charge or hydrophobicity of the molecule at the site of the substitution, and/or (c) the bulk of the side chain.

[0091] A “deletion” refers to a change in the amino acid or nucleotide sequence that results in the absence of one or more amino acid residues or nucleotides.

[0092] The term “derivative” refers to a chemically modified polynucleotide or polypeptide. Chemical modifications of a polynucleotide can include, for example, replacement of hydrogen by an alkyl, acyl, hydroxyl, or amino group. A derivative polynucleotide encodes a polypeptide which retains at least one biological or immunological function of the natural molecule. A derivative polypeptide is one modified by glycosylation, pegylation, or any similar process that retains at least one biological or immunological function of the polypeptide from which it was derived.

[0093] A “detectable label” refers to a reporter molecule or enzyme that is capable of generating a measurable signal and is covalently or noncovalently joined to a polynucleotide or polypeptide.

[0094] “Differential expression” refers to increased or upregulated; or decreased, downregulated, or absent gene or protein expression, determined by comparing at least two different samples. Such comparisons may be carried out between, for example, a treated and an untreated sample, or a diseased and a normal sample.

[0095] “Exon shuffling” refers to the recombination of different coding regions (exons). Since an exon may represent a structural or functional domain of the encoded protein, new proteins may be assembled through the novel reassortment of stable substructures, thus allowing acceleration of the evolution of new protein functions.

[0096] A “fragment” is a unique portion of SECP or a polynucleotide encoding SECP which can be identical in sequence to, but shorter in length than, the parent sequence. A fragment may comprise up to the entire length of the defined sequence, minus one nucleotide/amino acid residue. For example, a fragment may comprise from about 5 to about 1000 contiguous nucleotides or amino acid residues. A fragment used as a probe, primer, antigen, therapeutic molecule, or for other purposes, may be at least 5, 10, 15, 16, 20, 25, 30, 40, 50, 60, 75, 100, 150, 250 or at least 500 contiguous nucleotides or amino acid residues in length. Fragments may be preferentially selected from certain regions of a molecule. For example, a polypeptide fragment may comprise a certain length of contiguous amino acids selected from the first 250 or 500 amino acids (or first 25% or 50%) of a polypeptide as shown in a certain defined sequence. Clearly these lengths are exemplary, and any length that is supported by the specification, including the Sequence Listing, tables, and figures, may be encompassed by the present embodiments.

[0097] A fragment of SEQ ID NO:32-62 can comprise a region of unique polynucleotide sequence that specifically identifies SEQ ID NO:32-62, for example, as distinct from any other sequence in the genome from which the fragment was obtained. A fragment of SEQ ID NO:32-62 can be employed in one or more embodiments of methods of the invention, for example, in hybridization and amplification technologies and in analogous methods that distinguish SEQ ID NO:32-62 from related polynucleotides. The precise length of a fragment of SEQ ID NO:32-62 and the region of SEQ ID NO:32-62 to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment.

[0098] A fragment of SEQ ID NO:1-31 is encoded by a fragment of SEQ ID NO:32-62. A fragment of SEQ ID NO:1-31 can comprise a region of unique amino acid sequence that specifically identifies SEQ ID NO:1-31. For example, a fragment of SEQ ID NO:1-31 can be used as an immunogenic peptide for the development of antibodies that specifically recognize SEQ ID NO:1-31. The precise length of a fragment of SEQ ID NO:1-31 and the region of SEQ ID NO:1-31 to which the fragment corresponds can be determined based on the intended purpose for the fragment using one or more analytical methods described herein or otherwise known in the art.

[0099] A “full length” polynucleotide is one containing at least a translation initiation codon (e.g., methionine) followed by an open reading frame and a translation termination codon. A “full length” polynucleotide sequence encodes a “full length” polypeptide sequence.

[0100] “Homology” refers to sequence similarity or, interchangeably, sequence identity, between two or more polynucleotide sequences or two or more polypeptide sequences.

[0101] The terms “percent identity” and “% identity,” as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide sequences aligned using a standardized algorithm Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences.

[0102] Percent identity between polynucleotide sequences may be determined using one or more computer algorithms or programs known in the art or described herein. For example, percent identity can be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN version 3.12e sequence alignment program. This program is part of the LASERGENE software package, a suite of molecular biological analysis programs (DNASTAR, Madison Wis.). CLUSTAL V is described in Higgins, D. G. and P. M. Sharp (1989; CABIOS 5:151-153) and in Higgins, D. G. et al. (1992; CABIOS 8:189-191). For pairwise alignments of polynucleotide sequences, the default parameters are set as follows: Ktuple=2, gap penalty=5, window=4, and “diagonals saved”=4. The “weighted” residue weight table is selected as the default. Percent identity is reported by CLUSTAL V as the “percent similarity” between aligned polynucleotide sequences.

[0103] Alternatively, a suite of commonly used and freely available sequence comparison algorithms which can be used is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403-410), which is available from several sources, including the NCBI, Bethesda, Md., and on the Internet at http://www.ncbi.nlm.nih.gov/BLAST/. The BLAST software suite includes various sequence analysis programs including “blastn,” that is used to align a known polynucleotide sequence with other polynucleotide sequences from a variety of databases. Also available is a tool called “BLAST 2 Sequences” that is used for direct pairwise comparison of two nucleotide sequences. “BLAST 2 Sequences” can be accessed and used interactively at http://www.ncbi.nlm.nih.gov/gorf/b12.html. The “BLAST 2 Sequences” tool can be used for both blastn and blastp (discussed below). BLAST programs are commonly used with gap and other parameters set to default settings. For example, to compare two nucleotide sequences, one may use blastn with the “BLAST 2 Sequences” tool Version 2.0.12 (Apr. 21, 2000) set at default parameters. Such default parameters may be, for example:

[0104] Matrix: BLOSUM62

[0105] Reward for match: 1

[0106] Penalty for mismatch: −2

[0107] Open Gap: 5 and Extension Gap: 2 penalties

[0108] Gap×drop-off: 50

[0109] Expect: 10

[0110] Word Size: 11

[0111] Filter: on

[0112] Percent identity may be measured over the length of an entire defined sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined sequence, for instance, a fragment of at least 20, at least 30, at least 40, at least 50, at least 70, at least 100, or at least 200 contiguous nucleotides. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures, or Sequence Listing, may be used to describe a length over which percentage identity may be measured.

[0113] Nucleic acid sequences that do not show a high degree of identity may nevertheless encode similar amino acid sequences due to the degeneracy of the genetic code. It is understood that changes in a nucleic acid sequence can be made using this degeneracy to produce multiple nucleic acid sequences that all encode substantially the same protein.

[0114] The phrases “percent identity” and “% identity,” as applied to polypeptide sequences, refer to the percentage of residue matches between at least two polypeptide sequences aligned using a standardized algorithm. Methods of polypeptide sequence alignment are well-known. Some alignment methods take into account conservative amino acid substitutions. Such conservative substitutions, explained in more detail above, generally preserve the charge and hydrophobicity at the site of substitution, thus preserving the structure (and therefore function) of the polypeptide.

[0115] Percent identity between polypeptide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN version 3.12e sequence alignment program (described and referenced above). For pairwise alignments of polypeptide sequences using CLUSTAL V, the default parameters are set as follows: Ktuple=1, gap penalty=3, window=5, and “diagonals saved”=5. The PAM250 matrix is selected as the default residue weight table. As with polynucleotide alignments, the percent identity is reported by CLUSTAL V as the “percent similarity” between aligned polypeptide sequence pairs.

[0116] Alternatively the NCBI BLAST software suite may be used. For example, for a pairwise comparison of two polypeptide sequences, one may use the “BLAST 2 Sequences” tool Version 2.0.12 (Apr. 21, 2000) with blastp set at default parameters. Such default parameters may be, for example:

[0117] Matrix: BLOSUM62

[0118] Open Gap: 11 and Extension Gap: 1 penalties

[0119] Gap×drop-off: 50

[0120] Expect: 10

[0121] Word Size: 3

[0122] Filter: on

[0123] Percent identity may be measured over the length of an entire defined polypeptide sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures or Sequence Listing, may be used to describe a length over which percentage identity may be measured.

[0124] “Human artificial chromosomes” (HACs) are linear microchromosomes which may contain DNA sequences of about 6 kb to 10 Mb in size and which contain all of the elements required for chromosome replication, segregation and maintenance.

[0125] The term “humanized antibody” refers to an antibody molecule in which the amino acid sequence in the non-antigen binding regions has been altered so that the antibody more closely resembles a human antibody, and still retains its original, binding ability.

[0126] “Hybridization” refers to the process by which a polynucleotide strand anneals with a complementary strand through base pairing under defined hybridization conditions. Specific hybridization is an indication that two nucleic acid sequences share a high degree of complementarity. Specific hybridization complexes form under permissive annealing conditions and remain hybridized after the “washing” step(s). The washing step(s) is particularly important in determining the stringency of the hybridization process, with more stringent conditions allowing less non-specific binding, i.e., binding between pairs of nucleic acid strands that are not perfectly matched. Permissive conditions for annealing of nucleic acid sequences are routinely determinable by one of ordinary skill in the art and may be consistent among hybridization experiments, whereas wash conditions may be varied among experiments to achieve the desired stringency, and therefore hybridization specificity. Permissive annealing conditions occur, for example, at 68° C. in the presence of about 6×SSC, about 1% (w/v) SDS, and about 100 μg/ml sheared, denatured salmon sperm DNA.

[0127] Generally, stringency of hybridization is expressed, in part, with reference to the temperature under which the wash step is carried out. Such wash temperatures are typically selected to be about 5° C. to 20° C. lower than the thermal melting point (T_(m)) for the specific sequence at a defined ionic strength and pH. The T_(m) is the temperature (under defined ionic strength and pH) at which 50% of the target sequence hybridizes to a perfectly matched probe. An equation for calculating T_(m) and conditions for nucleic acid hybridization are well known and can be found in Sambrook, J. et al., (1989) Molecular Cloning: A Laboratory Manual, 2^(nd) ed., vol. 1-3, Cold Spring Harbor Press, Plainview N.Y.; specifically see volume 2, chapter 9.

[0128] High stringency conditions for hybridization between polynucleotides of the present invention include wash conditions of 68° C. in the presence of about 0.2×SSC and about 0.1% SDS, for 1 hour. Alternatively, temperatures of about 65° C., 60° C., 55° C., or 42° C. may be used. SSC concentration may be varied from about 0.1 to 2×SSC, with SDS being present at about 0.1%. Typically, blocking reagents are used to block non-specific hybridization. Such blocking reagents include, for instance, sheared and denatured salmon sperm DNA at about 100-200 μg/ml. Organic solvent, such as formamide at a concentration of about 35-50% v/v, may also be used under particular circumstances, such as for RNA:DNA hybridizations. Useful variations on these wash conditions will be readily apparent to those of ordinary skill in the art. Hybridization, particularly under high stringency conditions, may be suggestive of evolutionary similarity between the nucleotides. Such similarity is strongly indicative of a similar role for the nucleotides and their encoded polypeptides.

[0129] The term “hybridization complex” refers to a complex formed between two nucleic acids by virtue of the formation of hydrogen bonds between complementary bases. A hybridization complex may be formed in solution (e.g., C₀t or R₀t analysis) or formed between one nucleic acid present in solution and another nucleic acid immobilized on a solid support (e.g., paper, membranes, filters, chips, pins or glass slides, or any other appropriate substrate to which cells or their nucleic acids have been fixed).

[0130] The words “insertion” and “addition” refer to changes in an amino acid or polynucleotide sequence resulting in the addition of one or more amino acid residues or nucleotides, respectively.

[0131] “Immune response” can refer to conditions associated with inflammation, trauma, immune disorders, or infectious or genetic disease, etc. These conditions can be characterized by expression of various factors, e.g., cytokines, chemokines, and other signaling molecules, which may affect cellular and systemic defense systems.

[0132] An “immunogenic fragment” is a polypeptide or oligopeptide fragment of SECP which is capable of eliciting an immune response when introduced into a living organism, for example, a mammal. The term “immunogenic fragment” also includes any polypeptide or oligopeptide fragment of SECP which is useful in any of the antibody production methods disclosed herein or known in the art.

[0133] The term “microarray” refers to an arrangement of a plurality of polynucleotides, polypeptides, antibodies, or other chemical compounds on a substrate.

[0134] The terms “element” and “array element” refer to a polynucleotide, polypeptide, antibody, or other chemical compound having a unique and defined position on a microarray.

[0135] The term “modulate” refers to a change in the activity of SECP. For example, modulation may cause an increase or a decrease in protein activity, binding characteristics, or any other biological, functional, or immunological properties of SECP.

[0136] The phrases “nucleic acid” and “nucleic acid sequence” refer to a nucleotide, oligonucleotide, polynucleotide, or any fragment thereof. These phrases also refer to DNA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA), or to any DNA-like or RNA-like material.

[0137] “Operably linked” refers to the situation in which a first nucleic acid sequence is placed in a functional relationship with a second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Operably linked DNA sequences may be in close proximity or contiguous and, where necessary to join two protein coding regions, in the same reading frame.

[0138] “Peptide nucleic acid” (PNA) refers to an antisense molecule or anti-gene agent which comprises an oligonucleotide of at least about 5 nucleotides in length linked to a peptide backbone of amino acid residues ending in lysine. The terminal lysine confers solubility to the composition. PNAs preferentially bind complementary single stranded DNA or RNA and stop transcript elongation, and may be pegylated to extend their lifespan in the cell.

[0139] “Post-translational modification” of an SECP may involve lipidation, glycosylation, phosphorylation, acetylation, racemization, proteolytic cleavage, and other modifications known in the art. These processes may occur synthetically or biochemically. Biochemical modifications will vary by cell type depending on the enzymatic milieu of SECP.

[0140] “Probe” refers to nucleic acids encoding SECP, their complements, or fragments thereof, which are used to detect identical, allelic or related nucleic acids. Probes are isolated oligonucleotides or polynucleotides attached to a detectable label or reporter molecule. Typical labels include radioactive isotopes, ligands, chemiluminescent agents, and enzymes. “Primers” are short nucleic acids, usually DNA oligonucleotides, which may be annealed to a target polynucleotide by complementary base-pairing. The primer may then be extended along the target DNA strand by a DNA polymerase enzyme. Primer pairs can be used for amplification (and identification) of a nucleic acid, e.g., by the polymerase chain reaction (PCR).

[0141] Probes and primers as used in the present invention typically comprise at least 15 contiguous nucleotides of a known sequence. In order to enhance specificity, longer probes and primers may also be employed, such as probes and primers that comprise at least 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, or at least 150 consecutive nucleotides of the disclosed nucleic acid sequences. Probes and primers may be considerably longer than these examples, and it is understood that any length supported by the specification, including the tables, figures, and Sequence Listing, may be used.

[0142] Methods for preparing and using probes and primers are described in the references, for example Sambrook, J. et al. (1989; Molecular Cloning: A Laboratory Manual, 2^(nd) ed., vol. 1-3, Cold Spring Harbor Press, Plainview N.Y.), Ausubel, F. M. et al. (1999) Short Protocols in Molecular Biology, 4^(th) ed., John Wiley & Sons, New York N.Y.), and Innis, M. et al. (1990; PCR Protocols, A Guide to Methods and Applications, Academic Press, San Diego Calif.). PCR primer pairs can be derived from a known sequence, for example, by using computer programs intended for that purpose such as Primer (Version 0.5, 1991, Whitehead Institute for Biomedical Research, Cambridge Mass.).

[0143] Oligonucleotides for use as primers are selected using software known in the art for such purpose. For example, OLIGO 4.06 software is useful for the selection of PCR primer pairs of up to 100 nucleotides each, and for the analysis of oligonucleotides and larger polynucleotides of up to 5,000 nucleotides from an input polynucleotide sequence of up to 32 kilobases. Similar primer selection programs have incorporated additional features for expanded capabilities. For example, the PrimOU primer selection program (available to the public from the Genome Center at University of Texas South West Medical Center, Dallas Tex.) is capable of choosing specific primers from megabase sequences and is thus useful for designing primers on a genome-wide scope. The Primer3 primer selection program. (available to the public from the Whitehead Institute/MIT Center for Genome Research, Cambridge Mass.) allows the user to input a “mispriming library,” in which sequences to avoid as primer binding sites are user-specified. Primer3 is useful; in particular, for the selection of oligonucleotides for microarrays. (The source code for the latter two primer selection programs may also be obtained from their respective sources and modified to meet the user's specific needs.) The PrimeGen program (available to the public from the UK Human Genome Mapping Project Resource Centre, Cambridge UK) designs primers based on multiple sequence alignments, thereby allowing selection of primers that hybridize to either the most conserved or least conserved regions of aligned nucleic acid sequences. Hence, this program is useful for identification of both unique and conserved oligonucleotides and polynucleotide fragments. The oligonucleotides and polynucleotide fragments identified by any of the above selection methods are useful in hybridization technologies, for example, as PCR or sequencing primers, microarray elements, or specific probes to identify fully or partially complementary polynucleotides in a sample of nucleic acids. Methods of oligonucleotide selection are not limited to those described above.

[0144] A “recombinant nucleic acid” is a nucleic acid that is not naturally occurring or has a sequence that is made by an artificial combination of two or more otherwise separated segments of sequence. This artificial combination is often accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques such as those described in Sambrook, supra. The term recombinant includes nucleic acids that have been altered solely by addition, substitution, or deletion of a portion of the nucleic acid. Frequently, a recombinant nucleic acid may include a nucleic acid sequence operably linked to a promoter sequence. Such a recombinant nucleic acid may be part of a vector that is used, for example, to transform a cell.

[0145] Alternatively, such recombinant nucleic acids may be part of a viral vector, e.g., based on a vaccinia virus, that could be use to vaccinate a mammal wherein the recombinant nucleic acid is expressed, inducing a protective immunological response in the mammal.

[0146] A “regulatory element” refers to a nucleic acid sequence usually derived from untranslated regions of a gene and includes enhancers, promoters, introns, and 5′ and 3′ untranslated regions (UTRs). Regulatory elements interact with host or viral proteins which control transcription, translation, or RNA stability.

[0147] “Reporter molecules” are chemical or biochemical moieties used for labeling a nucleic acid, amino acid, or antibody. Reporter molecules include radionuclides; enzymes; fluorescent, chemiluminescent, or chromogenic agents; substrates; cofactors; inhibitors; magnetic particles; and other moieties known in the art.

[0148] An “RNA equivalent,” in reference to a DNA molecule, is composed of the same linear sequence of nucleotides as the reference DNA molecule with the exception that all occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.

[0149] The term “sample” is used in its broadest sense. A sample suspected of containing SECP, nucleic acids encoding SECP, or fragments thereof may comprise a bodily fluid; an extract from a cell, chromosome, organelle, or membrane isolated from a cell; a cell; genomic DNA, RNA, or cDNA, in solution or bound to a substrate; a tissue; a tissue print; etc.

[0150] The terms “specific binding” and “specifically binding” refer to that interaction between a protein or peptide and an agonist, an antibody, an antagonist, a small molecule, or any natural or synthetic binding composition. The interaction is dependent upon the presence of a particular structure of the protein, e.g., the antigenic determinant or epitope, recognized by the binding molecule. For example, if an antibody is specific for epitope “A,” the presence of a polypeptide comprising the epitope A, or the presence of free unlabeled A, in a reaction containing free labeled A and the antibody will reduce the amount of labeled A that binds to the antibody.

[0151] The term “substantially purified” refers to nucleic acid or amino acid sequences that are removed from their natural environment and are isolated or separated, and are at least about 60% free, preferably at least about 75% free, and most preferably at least about 90% free from other components with which they are naturally associated.

[0152] A “substitution” refers to the replacement of one or more amino acid residues or nucleotides by different amino acid residues or nucleotides, respectively.

[0153] “Substrate” refers to any suitable rigid or semi-rigid support including membranes, filters, chips, slides, wafers, fibers, magnetic or nonmagnetic beads, gels, tubing, plates, polymers, microparticles and capillaries. The substrate can have a variety of surface forms, such as wells, trenches, pins, channels and pores, to which polynucleotides or polypeptides are bound.

[0154] A “transcript image” or “expression profile” refers to the collective pattern of gene expression by a particular cell type or tissue under given conditions at a given time.

[0155] “Transformation” describes a process by which exogenous DNA is introduced into a recipient cell. Transformation may occur under natural or artificial conditions according to various methods well known in the art, and may rely on any known method for the insertion of foreign nucleic acid sequences into a prokaryotic or eukaryotic host cell. The method for transformation is selected based on the type of host cell being transformed and may include, but is not limited to, bacteriophage or viral infection, electroporation, heat shock, lipofection, and particle bombardment. The term “transformed cells” includes stably transformed cells in which the inserted DNA is capable of replication either as an autonomously replicating plasmid or as part of the host chromosome, as well as transiently transformed cells which express the inserted DNA or RNA for limited periods of time.

[0156] A “transgenic organism,” as used herein, is any organism, including but not limited to animals and plants, in which one or more of the cells of the organism contains heterologous nucleic acid introduced by way of human intervention, such as by transgenic techniques well known in the art. The nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, such as by microinjection or by infection with a recombinant virus. In another embodiment, the nucleic acid can be introduced by infection with a recombinant viral vector, such as a lentiviral vector (Lois, C. et al. (2002) Science 295:868-872). The term genetic manipulation does not include classical cross-breeding, or in vitro fertilization, but rather is directed to the introduction of a recombinant DNA molecule. The transgenic organisms contemplated in accordance with the present invention include bacteria, cyanobacteria, fungi, plants and animals. The isolated DNA of the present invention can be introduced into the host by methods known in the art, for example infection, transfection, transformation or transconjugation. Techniques for transferring the DNA of the present invention into such organisms are widely known and provided in references such as Sambrook et al. (1989), supra.

[0157] A “variant” of a particular nucleic acid sequence is defined as a nucleic acid sequence having at least 40% sequence identity to the particular nucleic acid sequence over a certain length of one of the nucleic acid sequences using blastn with the “BLAST 2 Sequences” tool Version 2.0.9 (May 7, 1999) set at default parameters. Such a pair of nucleic acids may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length. A variant may be described as, for example, an “allelic” (as defined above), “splice,” “species,” or “polymorphic” variant. A splice variant may have significant identity to a reference molecule, but will generally have a greater or lesser number of polynucleotides due to alternate splicing of exons during mRNA processing. The corresponding polypeptide may possess additional functional domains or lack domains that are present in the reference molecule. Species variants are polynucleotides that vary from one species to another. The resulting polypeptides will generally have significant amino acid identity relative to each other. A polymorphic variant is a variation in the polynucleotide sequence of a particular gene between individuals of a given species. Polymorphic variants also may encompass “single nucleotide polymorphisms” (SNPs) in which the polynucleotide sequence varies by one nucleotide base. The presence of SNPs may be indicative of, for example, a certain population, a disease state, or a propensity for a disease state.

[0158] A “variant” of a particular polypeptide sequence is defined as a polypeptide sequence having at least 40% sequence identity to the particular polypeptide sequence over a certain length of one of the polypeptide sequences using blastp with the “BLAST 2 Sequences” tool Version 2.0.9 (May 7, 1999) set at default parameters. Such a pair of polypeptides may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length of one of the polypeptides.

The Invention

[0159] Various embodiments of the invention include new human secreted proteins (SECP), the polynucleotides encoding SECP, and the use of these compositions for the diagnosis, treatment, or prevention of cell proliferative, autoimmune/inflammatory, cardiovascular, neurological, and developmental disorders.

[0160] Table 1 summarizes the nomenclature for the full length polynucleotide and polypeptide embodiments of the invention. Each polynucleotide and its corresponding polypeptide are correlated to a single Incyte project identification number (Incyte Project ID). Each polypeptide sequence is denoted by both a polypeptide sequence identification number (Polypeptide SEQ ID NO:) and an Incyte polypeptide sequence number (Incyte Polypeptide ID) as shown. Each polynucleotide sequence is denoted by both a polynucleotide sequence identification number (Polynucleotide SEQ ID NO:) and an Incyte polynucleotide consensus sequence number (Incyte Polynucleotide ID) as shown. Column 6 shows the Incyte ID numbers of physical, full length clones corresponding to polypeptide and polynucleotide embodiments. The full length clones encode polypeptides which have at least 95% sequence identity to the polypeptides shown in column 3.

[0161] Table 2 shows sequences with homology to the polypeptides of the invention as identified by BLAST analysis against the GenBank protein (genpept) database. Columns 1 and 2 show the polypeptide sequence identification number (Polypeptide SEQ ID NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide ID) for polypeptides of the invention. Column 3 shows the GenBank identification number (GenBank ID NO:) of the nearest GenBank homolog. Column 4 shows the probability scores for the matches between each polypeptide and its homolog(s). Column 5 shows the annotation of the GenBank homolog(s) along with relevant citations where applicable, all of which are expressly incorporated by reference herein.

[0162] Table 3 shows various structural features of the polypeptides of the invention. Columns 1 and 2 show the polypeptide sequence identification number (SEQ ID NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide ID) for each polypeptide of the invention. Column 3 shows the number of amino acid residues in each polypeptide. Column 4 shows potential phosphorylation sites, and column 5 shows potential glycosylation sites, as determined by the MOTIFS program of the GCG sequence analysis software package (Genetics Computer Group, Madison Wis.). Column 6 shows amino acid residues comprising signature sequences, domains, and motifs. Column 7 shows analytical methods for protein structure/function analysis and in some cases, searchable databases to which the analytical methods were applied.

[0163] Together, Tables 2 and 3 summarize the properties of polypeptides of the invention, and these properties establish that the claimed polypeptides are secreted proteins. For example, SEQ ID NO:10 is 42% identical, from residue P31 to residue V133, to human putative progesterone binding protein (GenBank ID g2062022) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 2.4e-14, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. Data from additional BLAST analysis provide further corroborative evidence that SEQ ID NO:10 is a secreted protein. In an alternative example, SEQ ID NO:1 contains a fibronectin type III domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. Note that “fibronectin domains” are distinguishing motifs which are characteristic of matrix proteins, one type of secreted protein. (See Table 3.) In an alternative example, data from further BLAST analyses provide evidence that SEQ ID NO:13 is a secreted protein. (See Table 2.) In an alternative example, SEQ ID NO:18 is 95% identical, from residue M1 to residue R450, to Cercopithecus aetliiops growth/differentiation factor 7 (GenBank ID g13568984) as determined by BLAST. The BLAST probability score is 1.3e-228. (See Table 2.) SEQ ID NO:18 also contains a transforming growth factor beta like domain and a TGF-beta propeptide domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS, MOTIFS, and PROFILESCAN analyses provide further corroborative evidence that SEQ ID NO:18 is a TGF protein. In an alternative example, SEQ ID NO:25 is 86% identical, from residue M1 to residue P115, to human taxol resistant associated protein (GenBank ID g5019774) as determined by BLAST. The BLAST probability score is 2.2e-54. (See Table 2.) Data from HMMER, MOTIFS and other BLAST analyses provide further corroborative evidence that SEQ ID NO:25 is a secreted protein. (See Table 3.) In an alternative example, SEQ ID NO:26 is 34% identical, from residue V14 to residue E296, to human butyrophilin (GenBank ID g2062694) as determined by BLAST. The BLAST probability score is 1.5e-53. (See Table 2.) SEQ ID NO:26 also contains an immunoglobulin domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from addition BLAST analyses against the PRODOM database provide further corroborative evidence that SEQ ID NO:26 is a secreted protein. SEQ ID NO:2-9, SEQ ID NO:11-12, SEQ ID NO:14-17, SEQ ID NO:19-24, and SEQ ID NO:27-31 were analyzed and annotated in a similar manner. The algorithms and parameters for the analysis of SEQ ID NO:1-31 are described in Table 7.

[0164] As shown in Table 4, the full length polynucleotide embodiments were assembled using cDNA sequences or coding (exon) sequences derived from genomic DNA, or any combination of these two types of sequences. Column 1 lists the polynucleotide sequence identification number (Polynucleotide SEQ ID NO:), the corresponding Incyte polynucleotide consensus sequence number (Incyte ID) for each polynucleotide of the invention, and the length of each polynucleotide sequence in basepairs. Column 2 shows the nucleotide start (5′) and stop (3′) positions of the cDNA and/or genomic sequences used to assemble the full length polynucleotide embodiments, and of fragments of the polynucleotides which are useful, for example, in hybridization or amplification technologies that identify SEQ ID NO:32-62 or that distinguish between SEQ ID NO:32-62 and related polynucleotides.

[0165] The polynucleotide fragments described in Column 2 of Table 4 may refer specifically, for example, to Incyte cDNAs derived from tissue-specific cDNA libraries or from pooled cDNA libraries. Alternatively, the polynucleotide fragments described in column 2 may refer to GenBank cDNAs or ESTs which contributed to the assembly of the full length polynucleotides. In addition, the polynucleotide fragments described in column 2 may identify sequences derived from the ENSEMBL (The Sanger Centre, Cambridge, UK) database (i.e., those sequences including the designation “ENST”). Alternatively, the polynucleotide fragments described in column 2 may be derived from the NCBI RefSeq Nucleotide Sequence Records Database (i.e., those sequences including the designation “NM” or “NT”) or the NCBI RefSeq Protein Sequence Records (ie., those sequences including the designation “NP”). Alternatively, the polynucleotide fragments described in column 2 may refer to assemblages of both cDNA and Genscan-predicted exons brought together by an “exon stitching” algorithm. For example, a polynucleotide sequence identified as FL_XXXXXX_N_(2—)YYYYY_N_(3—)N₄ represents a “stitched” sequence in which XXXXXX is the identification number of the cluster of sequences to which the algorithm was applied, and YYYYY is the number of the prediction generated by the algorithm, and N_(1,2,3 . . .) , if present, represent specific exons that may have been manually edited during analysis (See Example V). Alternatively, the polynucleotide fragments in column 2 may refer to assemblages of exons brought together by an “exon-stretching” algorithm. For example, a polynucleotide sequence identified as FLXXXX_gAAAAA_gBBBBB_(—)1_N is a “stretched” sequence, with XXXXXX being the Incyte project identification number, gAAAAA being the GenBank identification number of the human genomic sequence to which the “exon-stretching” algorithm was applied, gBBBBB being the GenBank identification number or NCBI RefSeq identification number of the nearest GenBank protein homolog, and N referring to specific exons (See Example V). In instances where a RefSeq sequence was used as a protein homolog for the “exon-stretching” algorithm, a RefSeq identifier (denoted by “NM,” “NP,” or “NT”) may be used in place of the GenBank identifier (i.e., gBBBBB).

[0166] Alternatively, a prefix identifies component sequences that were hand-edited, predicted from genomic DNA sequences, or derived from a combination of sequence analysis methods. The following Table lists examples of component sequence prefixes and corresponding sequence analysis methods associated with the prefixes (see Example IV and Example V). Prefix Type of analysis and/or examples of programs GNN, Exon prediction from genomic sequences using, for GFG, example, GENSCAN (Stanford University, CA, USA) ENST or FGENES (Computer Genomics Group, The Sanger Centre, Cambridge, UK). GBI Hand-edited analysis of genomic sequences. FL Stitched or stretched genomic sequences (see Example V). INCY Full length transcript and exon prediction from mapping of EST sequences to the genome. Genomic location and EST composition data are combined to predict the exons and resulting transcript.

[0167] In some cases, Incyte cDNA coverage redundant with the sequence coverage shown in Table 4 was obtained to confirm the final consensus polynucleotide sequence, but the relevant Incyte cDNA identification numbers are not shown.

[0168] Table 5 shows the representative cDNA libraries for those full length polynucleotides which were assembled using Incyte cDNA sequences. The representative cDNA library is the Incyte cDNA library which is most frequently represented by the Incyte cDNA sequences which were used to assemble and confirm the above polynucleotides. The tissues and vectors which were used to construct the cDNA libraries shown in Table 5 are described in Table 6.

[0169] The invention also encompasses SECP variants. A preferred SECP variant is one which has at least about 80%, or alternatively at least about 90%, or even at least about 95% amino acid sequence identity to the SECP amino acid sequence, and which contains at least one functional or structural characteristic of SECP.

[0170] Various embodiments also encompass polynucleotides which encode SECP. In a particular embodiment, the invention encompasses a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID NO:32-62, which encodes SECP. The polynucleotide sequences of SEQ ID NO:32-62, as presented in the Sequence Listing, embrace the equivalent RNA sequences, wherein occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.

[0171] The invention also encompasses variants of a polynucleotide encoding SECP. In particular, such a variant polynucleotide will have at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to a polynucleotide encoding SECP. A particular aspect of the invention encompasses a variant of a polynucleotide comprising a sequence selected from the group consisting of SEQ ID NO:32-62 which has at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID NO:32-62. Any one of the polynucleotide variants described above can encode a polypeptide which contains at least one functional or structural characteristic of SECP.

[0172] In addition, or in the alternative, a polynucleotide variant of the invention is a splice variant of a polynucleotide encoding SECP. A splice variant may have portions which have significant sequence identity to a polynucleotide encoding SECP, but will generally have a greater or lesser number of polynucleotides due to additions or deletions of blocks of sequence arising from alternate splicing of exons during mRNA processing. A splice variant may have less than about 70%, or alternatively less than about 60%, or alternatively less than about 50% polynucleotide sequence identity to a polynucleotide encoding SECP over its entire length; however, portions of the splice variant will have at least about 70%, or alternatively at least about 85%, or alternatively at least about 95%, or alternatively 100% polynucleotide sequence identity to portions of the polynucleotide encoding SECP. For example, a polynucleotide comprising a sequence of SEQ ID NO:54 and a polynucleotide comprising a sequence of SEQ ID NO:62 are splice variants of each other. Any one of the splice variants described above can encode a polypeptide which contains at least one functional or structural characteristic of SECP.

[0173] It will be appreciated by those skilled in the art that as a result of the degeneracy of the genetic code, a multitude of polynucleotide sequences encoding SECP, some bearing minimal similarity to the polynucleotide sequences of any known and naturally occurring gene, may be produced. Thus, the invention contemplates each and every possible variation of polynucleotide sequence that could be made by selecting combinations based on possible codon choices. These combinations are made in accordance with the standard triplet genetic code as applied to the polynucleotide sequence of naturally occurring SECP, and all such variations are to be considered as being specifically disclosed.

[0174] Although polynucleotides which encode SECP and its variants are generally capable of hybridizing to polynucleotides encoding naturally occurring SECP under appropriately selected conditions of stringency, it may be advantageous to produce polynucleotides encoding SECP or its derivatives possessing a substantially different codon usage, e.g., inclusion of non-naturally occurring codons. Codons may be selected to increase the rate at which expression of the peptide occurs in a particular prokaryotic or eukaryotic host in accordance with the frequency with which particular codons are utilized by the host. Other reasons for substantially altering the nucleotide sequence encoding SECP and its derivatives without altering the encoded amino acid sequences include the production of RNA transcripts having more desirable properties, such as a greater half-life, than transcripts produced from the naturally occurring sequence.

[0175] The invention also encompasses production of polynucleotides which encode SECP and SECP derivatives, or fragments thereof, entirely by synthetic chemistry. After production, the synthetic polynucleotide may be inserted into any of the many available expression vectors and cell systems using reagents well known in the art. Moreover, synthetic chemistry may be used to introduce mutations into a polynucleotide encoding SECP or any fragment thereof.

[0176] Embodiments of the invention can also include polynucleotides that are capable of hybridizing to the claimed polynucleotides, and, in particular, to those having the sequences shown in SEQ ID NO:32-62 and fragments thereof, under various conditions of stringency (Wahl, G. M. and S. L. Berger (1987) Methods Enzymol. 152:399-407; Kimmel, A. R. (1987) Methods Enzymol. 152:507-511). Hybridization conditions, including annealing and wash conditions, are described in “Definitions.”

[0177] Methods for DNA sequencing are well known in the art and may be used to practice any of the embodiments of the invention. The methods may employ such enzymes as the Klenow fragment of DNA polymerase I, SEQUENASE (US Biochemical, Cleveland Ohio), Taq polymerase (Applied Biosystems), thermostable T7 polymerase (Amersham Biosciences, Piscataway N.J.), or combinations of polymerases and proofreading exonucleases such as those found in the ELONGASE amplification system (Invitrogen, Carlsbad Calif.). Preferably, sequence preparation is automated with machines such as the MICROLAB 2200 liquid transfer system (Hamilton, Reno Nev.), PTC200 thermal cycler (MJ Research, Watertown Mass.) and ABI CATALYST 800 thermal cycler (Applied Biosystems). Sequencing is then carried out using either the ABI 373 or 377 DNA sequencing system (Applied Biosystems), the MEGABACE 1000 DNA sequencing system (Amersham Biosciences), or other systems known in the art. The resulting sequences are analyzed using a variety of algorithms which are well known in the art (Ausubel et al., supra, ch. 7; Meyers, R. A. (1995) Molecular Biology and Biotechnology, Wiley V C H, New York N.Y., pp. 856-853).

[0178] The nucleic acids encoding SECP may be extended utilizing a partial nucleotide sequence and employing various PCR-based methods known in the art to detect upstream sequences, such as promoters and regulatory elements. For example, one method which may be employed, restriction-site PCR, uses universal and nested primers to amplify unknown sequence from genomic DNA within a cloning vector (Sarkar, G. (1993) PCR Methods Applic. 2:318-322). Another method, inverse PCR, uses primers that extend in divergent directions to amplify unknown sequence from a circularized template. The template is derived from restriction fragments comprising a known genomic locus and surrounding sequences (Triglia, T. et al. (1988) Nucleic Acids Res. 16:8186). A third method, capture PCR, involves PCR amplification of DNA fragments adjacent to known sequences in human and yeast artificial chromosome DNA (Lagerstrom, M. et al. (1991) PCR Methods Applic. 1: 111-119). In this method, multiple restriction enzyme digestions and ligations may be used to insert an engineered double-stranded sequence into a region of unknown sequence before performing PCR. Other methods which may be used to retrieve unknown sequences are known in the art (Parker, J. D. et al. (1991) Nucleic Acids Res. 19:3055-3060). Additionally, one may use PCR, nested primers, and PROMOTERFINDER libraries (Clontech, Palo Alto Calif.) to walk genomic DNA. This procedure avoids the need to screen libraries and is useful in finding intron/exon junctions. For all PCR-based methods, primers may be designed using commercially available software, such as OLIGO 4.06 primer analysis software (National Biosciences, Plymouth Minn.) or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the template at temperatures of about 68° C. to 72° C.

[0179] When screening for full length cDNAs, it is preferable to use libraries that have been size-selected to include larger cDNAs. In addition, random-primed libraries, which often include sequences containing the 5′ regions of genes, are preferable for situations in which an oligo d(T) library does not yield a full-length cDNA. Genomic libraries may be useful for extension of sequence into 5′ non-transcribed regulatory regions.

[0180] Capillary electrophoresis systems which are commercially available may be used to analyze the size or confirm the nucleotide sequence of sequencing or PCR products. In particular, capillary sequencing may employ flowable polymers for electrophoretic separation, four different nucleotide-specific, laser-stimulated fluorescent dyes, and a charge coupled device camera for detection of the emitted wavelengths. Output/light intensity may be converted to electrical signal using appropriate software (e.g., GENOTYPER and SEQUENCE NAVIGATOR, Applied Biosystems), and the entire process from loading of samples to computer analysis and electronic data display may be computer controlled. Capillary electrophoresis is especially preferable for sequencing small DNA fragments which may be present in limited amounts in a particular sample.

[0181] In another embodiment of the invention, polynucleotides or fragments thereof which encode SECP may be cloned in recombinant DNA molecules that direct expression of SECP, or fragments or functional equivalents thereof, in appropriate host cells. Due to the inherent degeneracy of the genetic code, other polynucleotides which encode substantially the same or a functionally equivalent polypeptides may be produced and used to express SECP.

[0182] The polynucleotides of the invention can be engineered using methods generally known in the art in order to alter SECP-encoding sequences for a variety of purposes including, but not limited to, modification of the cloning, processing, and/or expression of the gene product. DNA shuffling by random fragmentation and PCR reassembly of gene fragments and synthetic oligonucleotides may be used to engineer the nucleotide sequences. For example, oligonucleotide-mediated site-directed mutagenesis may be used to introduce mutations that create new restriction sites, alter glycosylation patterns, change codon preference, produce splice variants, and so forth.

[0183] The nucleotides of the present invention may be subjected to DNA shuffling techniques such as MOLECULARBREEDING (Maxygen Inc., Santa Clara Calif.; described in U.S. Pat. No. 5,837,458; Chang, C.-C. et al. (1999) Nat. Biotechnol. 17:793-797; Christians, F. C. et al. (1999) Nat. Biotechnol. 17:259-264; and Crameri, A. et al. (1996) Nat. Biotechnol. 14:315-319) to alter or improve the biological properties of SECP, such as its biological or enzymatic activity or its ability to bind to other molecules or compounds. DNA shuffling is a process by which a library of gene variants is produced using PCR-mediated recombination of gene fragments. The library is then subjected to selection or screening procedures that identify those gene variants with the desired properties. These preferred variants may then be pooled and further subjected to recursive rounds of DNA shuffling and selection/screening. Thus, genetic diversity is created through “artificial” breeding and rapid molecular evolution. For example, fragments of a single gene containing random point mutations may be recombined, screened, and then reshuffled until the desired properties are optimized. Alternatively, fragments of a given gene may be recombined with fragments of homologous genes in the same gene family, either from the same or different species, thereby maximizing the genetic diversity of multiple naturally occurring genes in a directed and controllable manner.

[0184] In another embodiment, polynucleotides encoding SECP may be synthesized, in whole or in part, using one or more chemical methods well known in the art (Caruthers, M. H. et al. (1980) Nucleic Acids Symp. Ser. 7:215-223; Horn, T. et al. (1980) Nucleic Acids Symp. Ser. 7:225-232). Alternatively, SECP itself or a fragment thereof may be synthesized using chemical methods known in the art. For example, peptide synthesis can be performed using various solution-phase or solid-phase techniques (Creighton, T. (1984) Proteins, Structures and Molecular Properties, W H Freeman, New York N.Y., pp. 55-60; Roberge, J. Y. et al. (1995) Science 269:202-204). Automated synthesis may be achieved using the ABI 431A peptide synthesizer (Applied Biosystems). Additionally, the amino acid sequence of SECP, or any part thereof, may be altered during direct synthesis and/or combined with sequences from other proteins, or any part thereof, to produce a variant polypeptide or a polypeptide having a sequence of a naturally occurring polypeptide.

[0185] The peptide may be substantially purified by preparative high performance liquid chromatography (Chiez, R. M. and F. Z. Regnier (1990) Methods Enzymol. 182:392-421). The composition of the synthetic peptides may be confirmed by amino acid analysis or by sequencing. (Creighton, supra, pp. 28-53).

[0186] In order to express a biologically active SECP, the polynucleotides encoding SECP or derivatives thereof may be inserted into an appropriate expression vector, i.e., a vector which contains the necessary elements for transcriptional and translational control of the inserted coding sequence in a suitable host. These elements include regulatory sequences, such as enhancers, constitutive and inducible promoters, and 5′ and 3′ untranslated regions in the vector and in polynucleotides encoding SECP. Such elements may vary in their strength and specificity. Specific initiation signals may also be used to achieve more efficient translation of polynucleotides encoding SECP. Such signals include the ATG initiation codon and adjacent sequences, e.g. the Kozak sequence. In cases where a polynucleotide sequence encoding SECP and its initiation codon and upstream regulatory sequences are inserted into the appropriate expression vector, no additional transcriptional or translational control signals may be needed. However, in cases where only coding sequence, or a fragment thereof, is inserted, exogenous translational control signals including an in-frame ATG initiation codon should be provided by the vector. Exogenous translational elements and initiation codons may be of various origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of enhancers appropriate for the particular host cell system used (Scharf, D. et al. (1994) Results Probl. Cell Differ. 20:125-162).

[0187] Methods which are well known to those skilled in the art may be used to construct expression vectors containing polynucleotides encoding SECP and appropriate transcriptional and translational control elements. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination (Sambrook, J. et al. (1989) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Plainview N.Y., ch. 4, 8, and 16-17; Ausubel et al., supra, ch. 1, 3, and 15).

[0188] A variety of expression vector/host systems may be utilized to contain and express polynucleotides encoding SECP. These include, but are not limited to, microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid DNA expression vectors; yeast transformed with yeast expression vectors; insect cell systems infected with viral expression vectors (e.g., baculovirus); plant cell systems transformed with viral expression vectors (e.g., cauliflower mosaic virus, CaMV, or tobacco mosaic virus, TMV) or with bacterial expression vectors (e.g., Ti or pBR322 plasmids); or animal cell systems (Sambrook, supra; Ausubel et al., supra; Van Heeke, G. and S. M. Schuster (1989) J. Biol. Chem. 264:5503-5509; Engelhard, E. K. et al. (1994) Proc. Natl. Acad. Sci. USA 91:3224-3227; Sandig, V. et al. (1996) Hum. Gene Ther. 7:1937-1945; Takamatsu, N. (1987) EMBO J. 6:307-311; The McGraw Hill Yearbook of Science and Technology (1992) McGraw Hill, New York N.Y., pp. 191-196; Logan, J. and T. Shenk (1984) Proc. Natl. Acad. Sci. USA 81:3655-3659; Harrington, J. J. et al. (1997) Nat. Genet. 15:345-355). Expression vectors derived from retroviruses, adenoviruses, or herpes or vaccinia viruses, or from various bacterial plasmids, may be used for delivery of polynucleotides to the targeted organ, tissue, or cell population (Di Nicola, M. et al. (1998) Cancer Gen. Ther. 5:350-356; Yu, M. et al. (1993) Proc. Natl. Acad. Sci. USA 90:6340-6344; Buller, R. M. et al. (1985) Nature 317:813-815; McGregor, D. P. et al. (1994) Mol. Immunol. 31:219-226; Verma, I. M. and N. Somia (1997) Nature 389:239-242). The invention is not limited by the host cell employed.

[0189] In bacterial systems, a number of cloning and expression vectors may be selected depending upon the use intended for polynucleotides encoding SECP. For example, routine cloning, subcloning, and propagation of polynucleotides encoding SECP can be achieved using a multifunctional E. coli vector such as PBLUESCRIPT (Stratagene, La Jolla Calif.) or PSPORT1 plasmid (Invitrogen). Ligation of polynucleotides encoding SECP into the vector's multiple cloning site disrupts the lacZ gene, allowing a colorimetric screening procedure for identification of transformed bacteria containing recombinant molecules. In addition, these vectors may be useful for in vitro transcription, dideoxy sequencing, single strand rescue with helper phage, and creation of nested deletions in the cloned sequence (Van Heeke, G. and S. M. Schuster (1989) J. Biol. Chem. 264:5503-5509). When large quantities of SECP are needed, e.g. for the production of antibodies, vectors which direct high level expression of SECP may be used. For example, vectors containing the strong, inducible SP6 or T7 bacteriophage promoter may be used.

[0190] Yeast expression systems may be used for production of SECP. A number of vectors containing constitutive or inducible promoters, such as alpha factor, alcohol oxidase, and PGH promoters, may be used in the yeast Saccharomyces cerevisiae or Pichia pastoris. In addition, such vectors direct either the secretion or intracellular retention of expressed proteins and enable integration of foreign polynucleotide sequences into the host genome for stable propagation (Ausubel et al., supra; Bitter, G. A. et al. (1987) Methods Enzymol. 153:516-544; Scorer, C. A. et al. (1994) Bio/Technology 12:181-184).

[0191] Plant systems may also be used for expression of SECP. Transcription of polynucleotides encoding SECP may be driven by viral promoters, e.g., the 35S and 19S promoters of CaMV used alone or in combination with the omega leader sequence from TMV (Takamatsu, N. (1987) EMBO J. 6:307-311). Alternatively, plant promoters such as the small subunit of RUBISCO or heat shock promoters may be used (Coruzzi, G. et al. (1984) EMBO J. 3:1671-1680; Broglie, R. et al. (1984) Science 224:838-843; Winter, J. et al. (1991) Results Probl. Cell Differ. 17:85-105). These constructs can be introduced into plant cells by direct DNA transformation or pathogen-mediated transfection (The McGraw Hill Yearbook of Science and Technology (1992) McGraw Hill, New York N.Y., pp. 191-196).

[0192] In mammalian cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, polynucleotides encoding SECP may be ligated into an adenovirus transcription/translation complex consisting of the late promoter and tripartite leader sequence. Insertion in a non-essential E1 or E3 region of the viral genome may be used to obtain infective virus which expresses SECP in host cells (Logan, J. and T. Shenk (1984) Proc. Natl. Acad. Sci. USA 81:3655-3659). In addition, transcription enhancers, such as the Rous sarcoma virus (RSV) enhancer, may be used to increase expression in mammalian host cells. SV40 or EBV-based vectors may also be used for high-level protein expression.

[0193] Human artificial chromosomes (HACs) may also be employed to deliver larger fragments of DNA than can be contained in and expressed from a plasmid. HACs of about 6 kb to 10 Mb are constructed and delivered via conventional delivery methods (liposomes, polycationic amino polymers, or vesicles) for therapeutic purposes (Harrington, J. J. et al. (1997) Nat. Genet. 15:345-355).

[0194] For long term production of recombinant proteins in mammalian systems, stable expression of SECP in cell lines is preferred. For example, polynucleotides encoding SECP can be transformed into cell lines using expression vectors which may contain viral origins of replication and/or endogenous expression elements and a selectable marker gene on the same or on a separate vector. Following the introduction of the vector, cells may be allowed to grow for about 1 to 2 days in enriched media before being switched to selective media. The purpose of the selectable marker is to confer resistance to a selective agent, and its presence allows growth and recovery of cells which successfully express the introduced sequences. Resistant clones of stably transformed cells may be propagated using tissue culture techniques appropriate to the cell type.

[0195] Any number of selection systems may be used to recover transformed cell lines. These include, but are not limited to, the herpes simplex virus thymidine kinase and adenine phosphoribosyltransferase genes, for use in tk⁻ and apr⁻ cells, respectively (Wigler, M. et al. (1977) Cell 11:223-232; Lowy, I. et al. (1980) Cell 22:817-823). Also, antimetabolite, antibiotic, or herbicide resistance can be used as the basis for selection. For example, dhfr confers resistance to methotrexate; neo confers resistance to the aminoglycosides neomycin and G418; and als and pat confer resistance to chlorsulfuron and phosphinotricin acetyltransferase, respectively (Wigler, M. et al. (1980) Proc. Natl. Acad. Sci. USA 77:3567-3570; Colbere-Garapin, F. et al. (1981) J. Mol. Biol. 150:1-14). Additional selectable genes have been described, e.g., trpB and hisD, which alter cellular requirements for metabolites (Hartman, S. C. and R. C. Mulligan (1988) Proc. Natl. Acad. Sci. USA 85:8047-8051). Visible markers, e.g., anthocyanins, green fluorescent proteins (GFP; Clontech), β-glucuronidase and its substrate β-glucuronide, or luciferase and its substrate luciferin may be used. These markers can be used not only to identify transformants, but also to quantify the amount of transient or stable protein expression attributable to a specific vector system (Rhodes, C. A. (1995) Methods Mol. Biol. 55:121-131).

[0196] Although the presence/absence of marker gene expression suggests that the gene of interest is also present, the presence and expression of the gene may need to be confirmed. For example, if the sequence encoding SECP is inserted within a marker gene sequence, transformed cells containing polynucleotides encoding SECP can be identified by the absence of marker gene function. Alternatively, a marker gene can be placed in tandem with a sequence encoding SECP under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well.

[0197] In general, host cells that contain the polynucleotide encoding SECP and that express SECP may be identified by a variety of procedures known to those of skill in the art. These procedures include, but are not limited to, DNA-DNA or DNA-RNA hybridizations, PCR amplification, and protein bioassay or immunoassay techniques which include membrane, solution, or chip based technologies for the detection and/or quantification of nucleic acid or protein sequences.

[0198] Immunological methods for detecting and measuring the expression of SECP using either specific polyclonal or monoclonal antibodies are known in the art. Examples of such techniques include enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), and fluorescence activated cell sorting (FACS). A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering epitopes on SECP is preferred, but a competitive binding assay may be employed. These and other assays are well known in the art (Hampton, R. et al. (1990) Serological Methods, a Laboratory Manual, APS Press, St. Paul Minn., Sect. IV; Coligan, J. E. et al. (1997) Current Protocols in Immunology, Greene Pub. Associates and Wiley-Interscience, New York N.Y.; Pound, J. D. (1998) Immunochemical Protocols, Humana Press, Totowa N.J.).

[0199] A wide variety of labels and conjugation techniques are known by those skilled in the art and may be used in various nucleic acid and amino acid assays. Means for producing labeled hybridization or PCR probes for detecting sequences related to polynucleotides encoding SECP include oligolabeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide. Alternatively, polynucleotides encoding SECP, or any fragments thereof, may be cloned into a vector for the production of an mRNA probe. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by addition of an appropriate RNA polymerase such as T7, T3, or SP6 and labeled nucleotides. These procedures may be conducted using a variety of commercially available kits, such as those provided by Amersham Biosciences, Promega (Madison Wis.), and US Biochemical. Suitable reporter molecules or labels which may be used for ease of detection include radionuclides, enzymes, fluorescent, chemiluminescent, or chromogenic agents, as well as substrates, cofactors, inhibitors, magnetic particles, and the like.

[0200] Host cells transformed with polynucleotides encoding SECP may be cultured under conditions suitable for the expression and recovery of the protein from cell culture. The protein produced by a transformed cell may be secreted or retained intracellularly depending on the sequence and/or the vector used. As will be understood by those of skill in the art, expression vectors containing polynucleotides which encode SECP may be designed to contain signal sequences which direct secretion of SECP through a prokaryotic or eukaryotic cell membrane.

[0201] In addition, a host cell strain may be chosen for its ability to modulate expression of the inserted polynucleotides or to process the expressed protein in the desired fashion. Such modifications of the polypeptide include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation. Post-translational processing which cleaves a “prepro” or “pro” form of the protein may also be used to specify protein targeting, folding, and/or activity. Different host cells which have specific cellular machinery and characteristic mechanisms for post-translational activities (e.g., CHO, HeLa, MDCK, HEK293, and WI38) are available from the American Type Culture Collection (ATCC, Manassas Va.) and may be chosen to ensure the correct modification and processing of the foreign protein.

[0202] In another embodiment of the invention, natural, modified, or recombinant polynucleotides encoding SECP may be ligated to a heterologous sequence resulting in translation of a fusion protein in any of the aforementioned host systems. For example, a chimeric SECP protein containing a heterologous moiety that can be recognized by a commercially available antibody may facilitate the screening of peptide libraries for inhibitors of SECP activity. Heterologous protein and peptide moieties may also facilitate purification of fusion proteins using commercially available affinity matrices. Such moieties include, but are not limited to, glutathione S-transferase (GST), maltose binding protein (MBP), thioredoxin (Trx), calmodulin binding peptide (CBP), 6-His, FLAG, c-myc, and hemagglutinin (HA). GST, MBP, Trx, CBP, and 6-His enable purification of their cognate fusion proteins on immobilized glutathione, maltose, phenylarsine oxide, calmodulin, and metal-chelate resins, respectively. FLAG, c-myc, and hemagglutinin (HA) enable immunoaffinity purification of fusion proteins using commercially available monoclonal and polyclonal antibodies that specifically recognize these epitope tags. A fusion protein may also be engineered to contain a proteolytic cleavage site located between the SECP encoding sequence and the heterologous protein sequence, so that SECP may be cleaved away from the heterologous moiety following purification. Methods for fusion protein expression and purification are discussed in Ausubel et al. (supra, ch. 10 and 16). A variety of commercially available kits may also be used to facilitate expression and purification of fusion proteins.

[0203] In another embodiment, synthesis of radiolabeled SECP may be achieved in vitro using the TNT rabbit reticulocyte lysate or wheat germ extract system (Promega). These systems couple transcription and translation of protein-coding sequences operably associated with the T7, T3, or SP6 promoters. Translation takes place in the presence of a radiolabeled amino acid precursor, for example, ³⁵S-methionine.

[0204] SECP, fragments of SECP, or variants of SECP may be used to screen for compounds that specifically bind to SECP. One or more test compounds may be screened for specific binding to SECP. In various embodiments, 1, 2, 3, 4, 5, 10, 20, 50, 100, or 200 test compounds can be screened for specific binding to SECP. Examples of test compounds can include antibodies, anticalins, oligonucleotides, proteins (e.g., ligands or receptors), or small molecules.

[0205] In related embodiments, variants of SECP can be used to screen for binding of test compounds, such as antibodies, to SECP, a variant of SECP, or a combination of SECP and/or one or more variants SECP. In an embodiment, a variant of SECP can be used to screen for compounds that bind to a variant of SECP, but not to SECP having the exact sequence of a sequence of SEQ ID NO:1-31. SECP variants used to perform such screening can have a range of about 50% to about 99% sequence identity to SECP, with various embodiments having 60%, 70%, 75%, 80%, 85%, 90%, and 95% sequence identity.

[0206] In an embodiment, a compound identified in a screen for specific binding to SECP can be closely related to the natural ligand of SECP, e.g., a ligand or fragment thereof, a natural substrate, a structural or functional mimetic, or a natural binding partner (Coligan, J. E. et al. (1991) Current Protocols in Immunology 1(2): Chapter 5). In another embodiment, the compound thus identified can be a natural ligand of a receptor SECP (Howard, A. D. et al. (2001) Trends Pharmacol. Sci. 22: 132-140; Wise, A. et al. (2002) Drug Discovery Today 7:235-246).

[0207] In other embodiments, a compound identified in a screen for specific binding to SECP can be closely related to the natural receptor to which SECP binds, at least a fragment of the receptor, or a fragment of the receptor including all or a portion of the ligand binding site or binding pocket. For example, the compound may be a receptor for SECP which is capable of propagating a signal, or a decoy receptor for SECP which is not capable of propagating a signal (Ashkenazi, A. and V. M. Divit (1999) Curr. Opin. Cell Biol. 11:255-260; Mantovani, A. et al. (2001) Trends Immunol. 22:328-336). The compound can be rationally designed using known techniques. Examples of such techniques include those used to construct the compound etanercept (ENBREL; Immunex Corp., Seattle Wash.), which is efficacious for treating rheumatoid arthritis in humans. Etanercept is an engineered p75 tumor necrosis factor (TNF) receptor dimer linked to the Fc portion of human IgG₁ (Taylor, P. C. et al. (2001) Curr. Opin. Immunol. 13:611-616).

[0208] In one embodiment, two or more antibodies having similar or, alternatively, different specificities can be screened for specific binding to SECP, fragments of SECP, or variants of SECP. The binding specificity of the antibodies thus screened can thereby be selected to identify particular fragments or variants of SECP. In one embodiment, an antibody can be selected such that its binding specificity allows for preferential identification of specific fragments or variants of SECP. In another embodiment, an antibody can be selected such that its binding specificity allows for preferential diagnosis of a specific disease or condition having increased, decreased, or otherwise abnormal production of SECP.

[0209] In an embodiment, anticalins can be screened for specific binding to SECP, fragments of SECP, or variants of SECP. Anticalins are ligand-binding proteins that have been constructed based on a lipocalin scaffold (Weiss, G. A. and H. B. Lowman (2000) Chem. Biol. 7:R177-R184; Skerra, A. (2001) J. Biotechnol. 74:257-275). The protein architecture of lipocalins can include a beta-barrel having eight antiparallel beta-strands, which supports four loops at its open end. These loops form the natural ligand-binding site of the lipocalins, a site which can be re-engineered in vitro by amino acid substitutions to impart novel binding specificities. The amino acid substitutions can be made using methods known in the art or described herein, and can include conservative substitutions (e.g., substitutions that do not alter binding specificity) or substitutions that modestly, moderately, or significantly alter binding specificity.

[0210] In one embodiment, screening for compounds which specifically bind to, stimulate, or inhibit SECP involves producing appropriate cells which express SECP, either as a secreted protein or on the cell membrane. Preferred cells include cells from mammals, yeast, Drosophila, or E. coli. Cells expressing SECP or cell membrane fractions which contain SECP are then contacted with a test compound and binding, stimulation, or inhibition of activity of either SECP or the compound is analyzed.

[0211] An assay may simply test binding of a test compound to the polypeptide, wherein binding is detected by a fluorophore, radioisotope, enzyme conjugate, or other detectable label. For example, the assay may comprise the steps of combining at least one test compound with SECP, either in solution or affixed to a solid support, and detecting the binding of SECP to the compound. Alternatively, the assay may detect or measure binding of a test compound in the presence of a labeled competitor. Additionally, the assay may be carried out using cell-free preparations, chemical libraries, or natural product mixtures, and the test compound(s) may be free in solution or affixed to a solid support.

[0212] An assay can be used to assess the ability of a compound to bind to its natural ligand and/or to inhibit the binding of its natural ligand to its natural receptors. Examples of such assays include radio-labeling assays such as those described in U.S. Pat. No. 5,914,236 and U.S. Pat. No. 6,372,724. In a related embodiment, one or more amino acid substitutions can be introduced into a polypeptide compound (such as a receptor) to improve or alter its ability to bind to its natural ligands (Matthews, D. J. and J. A. Wells. (1994) Chem. Biol. 1:25-30). In another related embodiment, one or more amino acid substitutions can be introduced into a polypeptide compound (such as a ligand) to improve or alter its ability to bind to its natural receptors (Cunningham, B. C. and J. A. Wells (1991) Proc. Natl. Acad. Sci. USA 88:3407-3411; Lowman, H. B. et al. (1991) J. Biol. Chem. 266:10982-10988).

[0213] SECP, fragments of SECP, or variants of SECP may be used to screen for compounds that modulate the activity of SECP. Such compounds may include agonists, antagonists, or partial or inverse agonists. In one embodiment, an assay is performed under conditions permissive for SECP activity, wherein SECP is combined with at least one test compound, and the activity of SECP in the presence of a test compound is compared with the activity of SECP in the absence of the test compound. A change in the activity of SECP in the presence of the test compound is indicative of a compound that modulates the activity of SECP. Alternatively, a test compound is combined with an in vitro or cell-free system comprising SECP under conditions suitable for SECP activity, and the assay is performed. In either of these assays, a test compound which modulates the activity of SECP may do so indirectly and need not come in direct contact with the test compound. At least one and up to a plurality of test compounds may be screened.

[0214] In another embodiment, polynucleotides encoding SECP or their mammalian homologs may be “knocked out” in an animal model system using homologous recombination in embryonic stem (ES) cells. Such techniques are well known in the art and are useful for the generation of animal models of human disease (see, e.g., U.S. Pat. No. 5,175,383 and U.S. Pat. No. 5,767,337). For example, mouse ES cells, such as the mouse 129/SvJ cell line, are derived from the early mouse embryo and grown in culture. The ES cells are transformed with a vector containing the gene of interest disrupted by a marker gene, e.g., the neomycin phosphotransferase gene (neo; Capecchi, M. R. (1989) Science 244:1288-1292). The vector integrates into the corresponding region of the host genome by homologous recombination. Alternatively, homologous recombination takes place using the Cre-loxP system to knockout a gene of interest in a tissue- or developmental stage-specific manner (Marth, J. D. (1996) Clin. Invest. 97:1999-2002; Wagner, K. U. et al. (1997) Nucleic Acids Res. 25:4323-4330). Transformed ES cells are identified and microinjected into mouse cell blastocysts such as those from the C57BL/6 mouse strain. The blastocysts are surgically transferred to pseudopregnant dams, and the resulting chimeric progeny are genotyped and bred to produce heterozygous or homozygous strains. Transgenic animals thus generated may be tested with potential therapeutic or toxic agents.

[0215] Polynucleotides encoding SECP may also be manipulated in vitro in ES cells derived from human blastocysts. Human ES cells have the potential to differentiate into at least eight separate cell lineages including endoderm, mesoderm, and ectodermal cell types. These cell lineages differentiate into, for example, neural cells, hematopoietic lineages, and cardiomyocytes (Thomson, J. A. et al. (1998) Science 282:1145-1147).

[0216] Polynucleotides encoding SECP can also be used to create “knockin” humanized animals (pigs) or transgenic animals (mice or rats) to model human disease. With knockin technology, a region of a polynucleotide encoding SECP is injected into animal ES cells, and the injected sequence integrates into the animal cell genome. Transformed cells are injected into blastulae, and the blastulae are implanted as described above. Transgenic progeny or inbred lines are studied and treated with potential pharmaceutical agents to obtain information on treatment of a human disease. Alternatively, a mammal inbred to overexpress SECP, e.g., by secreting SECP in its milk, may also serve as a convenient source of that protein (Janne, J. et al. (1998) Biotechnol. Annu. Rev. 4:55-74).

Therapeutics

[0217] Chemical and structural similarity, e.g., in the context of sequences and motifs, exists between regions of SECP and secreted proteins. In addition, examples of tissues expressing SECP can be found in Table 6 and can also be found in Example XI. Therefore, SECP appears to play a role in cell proliferative, autoimmune/inflammatory, cardiovascular, neurological, and developmental disorders. In the treatment of disorders associated with increased SECP expression or activity, it is desirable to decrease the expression or activity of SECP. In the treatment of disorders associated with decreased SECP expression or activity, it is desirable to increase the expression or activity of SECP.

[0218] Therefore, in one embodiment, SECP or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of SECP. Examples of such disorders include, but are not limited to, a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, a cancer of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus; an autoimmune/inflammatory disorder such as acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, and trauma; a cardiovascular disorder such as congestive heart failure, ischemic heart disease, angina pectoris, myocardial infarction, hypertensive heart disease, degenerative valvular heart disease, calcific aortic valve stenosis, congenitally bicuspid aortic valve, mitral annular calcification, mitral valve prolapse, rheumatic fever and rheumatic heart disease, infective endocarditis, nonbacterial thrombotic endocarditis, endocarditis of systemic lupus erythematosus, carcinoid heart disease, cardiomyopathy, myocarditis, pericarditis, neoplastic heart disease, congenital heart disease, complications of cardiac transplantation, arteriovenous fistula, atherosclerosis, hypertension, vasculitis, Raynaud's disease, aneurysms, arterial dissections, varicose veins, thrombophlebitis and phlebothrombosis, vascular tumors, and complications of thrombolysis, balloon angioplasty, vascular replacement, and coronary artery bypass graft surgery; a neurological disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, prion diseases including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorders of the central nervous system including Down syndrome, cerebral palsy, neuroskeletal disorders, autonomic nervous system disorders, cranial nerve disorders, spinal cord diseases, muscular dystrophy and other neuromuscular disorders, peripheral nervous system disorders, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis, mental disorders including mood, anxiety, and schizophrenic disorders, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, Tourette's disorder, progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia; and a developmental disorder such as renal tubular acidosis, anemia, Cushing's syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, epilepsy, gonadal dysgenesis, WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas, hereditary neuropathies such as Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as Syndenham's chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, and sensorineural hearing loss.

[0219] In another embodiment, a vector capable of expressing SECP or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of SECP including, but not limited to, those described above.

[0220] In a further embodiment, a composition comprising a substantially purified SECP in conjunction with a suitable pharmaceutical carrier may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of SECP including, but not limited to, those provided above.

[0221] In still another embodiment, an agonist which modulates the activity of SECP may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of SECP including, but not limited to, those listed above.

[0222] In a further embodiment, an antagonist of SECP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of SECP. Examples of such disorders include, but are not limited to, those cell proliferative, autoimmune/inflammatory, cardiovascular, neurological, and developmental disorders described above. In one aspect, an antibody which specifically binds SECP may be used directly as an antagonist or indirectly as a targeting or delivery mechanism for bringing a pharmaceutical agent to cells or tissues which express SECP.

[0223] In an additional embodiment, a vector expressing the complement of the polynucleotide encoding SECP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of SECP including, but not limited to, those described above.

[0224] In other embodiments, any protein, agonist, antagonist, antibody, complementary sequence, or vector embodiments may be administered in combination with other appropriate therapeutic agents. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.

[0225] An antagonist of SECP may be produced using methods which are generally known in the art. In particular, purified SECP may be used to produce antibodies or to screen libraries of pharmaceutical agents to identify those which specifically bind SECP. Antibodies to SECP may also be generated using methods that are well known in the art. Such antibodies may include, but are not limited to, polyclonal, monoclonal, chimeric, and single chain antibodies, Fab fragments, and fragments produced by a Fab expression library. Neutralizing antibodies (i.e., those which inhibit dimer formation) are generally preferred for therapeutic use. Single chain antibodies (e.g., from camels or llamas) may be potent enzyme inhibitors and may have advantages in the design of peptide mimetics, and in the development of immuno-adsorbents and biosensors (Muyldermans, S. (2001) J. Biotechnol. 74:277-302).

[0226] For the production of antibodies, various hosts including goats, rabbits, rats, mice, camels, dromedaries, llamas, humans, and others may be immunized by injection with SECP or with any fragment or oligopeptide thereof which has immunogenic properties. Depending on the host species, various adjuvants may be used to increase immunological response. Such adjuvants include, but are not limited to, Freund's, mineral gels such as aluminum hydroxide, and surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, KLH, and dinitrophenol. Among adjuvants used in humans, BCG (bacilli Calmette-Guerin) and Corynebacterium parvum are especially preferable.

[0227] It is preferred that the oligopeptides, peptides, or fragments used to induce antibodies to SECP have an amino acid sequence consisting of at least about 5 amino acids, and generally will consist of at least about 10 amino acids. It is also preferable that these oligopeptides, peptides, or fragments are identical to a portion of the amino acid sequence of the natural protein. Short stretches of SECP amino acids may be fused with those of another protein, such as KLH, and antibodies to the chimeric molecule may be produced.

[0228] Monoclonal antibodies to SECP may be prepared using any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique, the human B-cell hybridoma technique, and the EBV-hybridoma technique (Kohler, G. et al. (1975) Nature 256:495-497; Kozbor, D. et al. (1985) J. Immunol. Methods 81:31-42; Cote, R. J. et al. (1983) Proc. Natl. Acad. Sci. USA 80:2026-2030; Cole, S. P. et al. (1984) Mol. Cell Biol. 62:109-120).

[0229] In addition, techniques developed for the production of “chimeric antibodies,” such as the splicing of mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity, can be used (Morrison, S. L. et al. (1984) Proc. Natl. Acad. Sci. USA 81:6851-6855; Neuberger, M. S. et al. (1984) Nature 312:604-608; Takeda, S. et al. (1985) Nature 314:452-454). Alternatively, techniques described for the production of single chain antibodies may be adapted, using methods known in the art, to produce SECP-specific single chain antibodies. Antibodies with related specificity, but of distinct idiotypic composition, may be generated by chain shuffling from random combinatorial immunoglobulin libraries (Burton, D. R. (1991) Proc. Natl. Acad. Sci. USA 88:10134-10137).

[0230] Antibodies may also be produced by inducing in vivo production in the lymphocyte population or by screening immunoglobulin libraries or panels of highly specific binding reagents as disclosed in the literature (Orlandi, R. et al. (1989) Proc. Natl. Acad. Sci. USA 86:3833-3837; Winter, G. et al. (1991) Nature 349:293-299).

[0231] Antibody fragments which contain specific binding sites for SECP may also be generated. For example, such fragments include, but are not limited to, F(ab′)₂ fragments produced by pepsin digestion of the antibody molecule and Fab fragments generated by reducing the disulfide bridges of the F(ab′)2 fragments. Alternatively, Fab expression libraries may be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity (Huse, W. D. et al. (1989) Science 246:1275-1281).

[0232] Various immunoassays may be used for screening to identify antibodies having the desired specificity. Numerous protocols for competitive binding or immunoradiometric assays using either polyclonal or monoclonal antibodies with established specificities are well known in the art. Such immunoassays typically involve the measurement of complex formation between SECP and its specific antibody. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering SECP epitopes is generally used, but a competitive binding assay may also be employed (Pound, supra).

[0233] Various methods such as Scatchard analysis in conjunction with radioimmunoassay techniques may be used to assess the affinity of antibodies for SECP. Affinity is expressed as an association constant, K_(a), which is defined as the molar concentration of SECP-antibody complex divided by the molar concentrations of free antigen and free antibody under equilibrium conditions. The K_(a) determined for a preparation of polyclonal antibodies, which are heterogeneous in their affinities for multiple SECP epitopes, represents the average affinity, or avidity, of the antibodies for SECP. The K_(a) determined for a preparation of monoclonal antibodies, which are monospecific for a particular SECP epitope, represents a true measure of affinity. High-affinity antibody preparations with K_(a) ranging from about 10⁹ to 10¹² L/mole are preferred for use in immunoassays in which the SECP-antibody complex must withstand rigorous manipulations. Low-affinity antibody preparations with K_(a) ranging from about 10⁶ to 10⁷ L/mole are preferred for use in immunopurification and similar procedures which ultimately require dissociation of SECP, preferably in active form, from the antibody (Catty, D. (1988) Antibodies, Volume I: A Practical Approach, IRL Press, Washington D.C.; Liddell, J. E. and A. Cryer (1991) A Practical Guide to Monoclonal Antibodies, John Wiley & Sons, New York N.Y.).

[0234] The titer and avidity of polyclonal antibody preparations may be further evaluated to determine the quality and suitability of such preparations for certain downstream applications. For example, a polyclonal antibody preparation containing at least 1-2 mg specific antibody/ml, preferably 5-10 mg specific antibody/ml, is generally employed in procedures requiring precipitation of SECP-antibody complexes. Procedures for evaluating antibody specificity, titer, and avidity, and guidelines for antibody quality and usage in various applications, are generally available (Catty, supra; Coligan et al., supra).

[0235] In another embodiment of the invention, polynucleotides encoding SECP, or any fragment or complement thereof, may be used for therapeutic purposes. In one aspect, modifications of gene expression can be achieved by designing complementary sequences or antisense molecules (DNA, RNA, PNA, or modified oligonucleotides) to the coding or regulatory regions of the gene encoding SECP. Such technology is well known in the art, and antisense oligonucleotides or larger fragments can be designed from various locations along the coding or control regions of sequences encoding SECP (Agrawal, S., ed. (1996) Antisense Therapeutics, Humana Press, Totawa N.J.).

[0236] In therapeutic use, any gene delivery system suitable for introduction of the antisense sequences into appropriate target cells can be used. Antisense sequences can be delivered intracellularly in the form of an expression plasmid which, upon transcription, produces a sequence complementary to at least a portion of the cellular sequence encoding the target protein (Slater, J. E. et al. (1998) J. Allergy Clin. Immunol. 102:469-475; Scanlon, K. J. et al. (1995) 9:1288-1296). Antisense sequences can also be introduced intracellularly through the use of viral vectors, such as retrovirus and adeno-associated virus vectors (Miller, A. D. (1990) Blood 76:271; Ausubel et al., supra; Uckert, W. and W. Walther (1994) Pharmacol. Ther. 63:323-347). Other gene delivery mechanisms include liposome-derived systems, artificial viral envelopes, and other systems known in the art (Rossi, J. J. (1995) Br. Med. Bull. 51:217-225; Boado, R. J. et al. (1998) J. Pharm. Sci. 87:1308-1315; Morris, M. C. et al. (1997) Nucleic Acids Res. 25:2730-2736).

[0237] In another embodiment of the invention, polynucleotides encoding SECP may be used for somatic or germline gene therapy. Gene therapy may be performed to (i) correct a genetic deficiency (e.g., in the cases of severe combined immunodeficiency (SCID)-X1 disease characterized by X-linked inheritance (Cavazzana-Calvo, M. et al. (2000) Science 288:669-672), severe combined immunodeficiency syndrome associated with an inherited adenosine deaminase (ADA) deficiency (Blaese, R. M. et al. (1995) Science 270:475-480; Bordignon, C. et al. (1995) Science 270:470-475), cystic fibrosis (Zabner, J. et al. (1993) Cell 75:207-216; Crystal, R. G. et al. (1995) Hum. Gene Therapy 6:643-666; Crystal, R. G. et al. (1995) Hum. Gene Therapy 6:667-703), thalassamias, familial hypercholesterolemia, and hemophilia resulting from Factor VIII or Factor IX deficiencies (Crystal, R. G. (1995) Science 270:404-410; Verma, I. M. and N. Somia (1997) Nature 389:239-242)), (ii) express a conditionally lethal gene product (e.g., in the case of cancers which result from unregulated cell proliferation), or (iii) express a protein which affords protection against intracellular parasites (e.g., against human retroviruses, such as human immunodeficiency virus (HV) (Baltimore, D. (1988) Nature 335:395-396; Poeschla, E. et al. (1996) Proc. Natl. Acad. Sci. USA 93:11395-11399), hepatitis B or C virus (HBV, HCV); fungal parasites, such as Candida albicans and Paracoccidioides brasiliensis; and protozoan parasites such as Plasmodium falciparum and Trypanosoma cruzi). In the case where a genetic deficiency in SECP expression or regulation causes disease, the expression of SECP from an appropriate population of transduced cells may alleviate the clinical manifestations caused by the genetic deficiency.

[0238] In a further embodiment of the invention, diseases or disorders caused by deficiencies in SECP are treated by constructing mammalian expression vectors encoding SECP and introducing these vectors by mechanical means into SECP-deficient cells. Mechanical transfer technologies for use with cells in vivo or ex vitro include (i) direct DNA microinjection into individual cells, (ii) ballistic gold particle delivery, (iii) liposome-mediated transfection, (iv) receptor-mediated gene transfer, and (v) the use of DNA transposons (Morgan, R. A. and W. F. Anderson (1993) Annu. Rev. Biochem. 62:191-217; Ivics, Z. (1997) Cell 91:501-510; Boulay, J.-L. and H. Recipon (1998) Curr. Opin. Biotechnol. 9:445-450).

[0239] Expression vectors that may be effective for the expression of SECP include, but are not limited to, the PCDNA 3.1, EPITAG, PRCCMV2, PREP, PVAX, PCR2-TOPOTA vectors (Invitrogen, Carlsbad Calif.), PCMV-SCRIPT, PCMV-TAG, PEGSH/PERV (Stratagene, La Jolla Calif.), and PTET-OFF, PTET-ON, PTRE2, PTRE2-LUC, PTK-HYG (Clontech, Palo Alto Calif.). SECP may be expressed using (i) a constitutively active promoter, (e.g., from cytomegalovirus (CMV), Rous sarcoma virus (RSV), SV40 virus, thymidine kinase (TK), or β-actin genes), (ii) an inducible promoter (e.g., the tetracycline-regulated promoter (Gossen, M. and H. Bujard (1992) Proc. Natl. Acad. Sci. USA 89:5547-5551; Gossen, M. et al. (1995) Science 268:1766-1769; Rossi, F. M. V. and H. M. Blau (1998) Curr. Opin. Biotechnol. 9:451-456), commercially available in the T-REX plasmid (Invitrogen)); the ecdysone-inducible promoter (available in the plasmids PVGRXR and PIND; Invitrogen); the FK506/rapamycin inducible promoter; or the RU486/mifepristone inducible promoter (Rossi, F. M. V. and H. M. Blau, supra)), or (iii) a tissue-specific promoter or the native promoter of the endogenous gene encoding SECP from a normal individual.

[0240] Commercially available liposome transformation kits (e.g., the PERFECT LIPID TRANSFECTION KIT, available from Invitrogen) allow one with ordinary skill in the art to deliver polynucleotides to target cells in culture and require minimal effort to optimize experimental parameters. In the alternative, transformation is performed using the calcium phosphate method (Graham, F. L. and A. J. Eb (1973) Virology 52:456467), or by electroporation (Neumann, E. et al. (1982) EMBO J. 1:841-845). The introduction of DNA to primary cells requires modification of these standardized mammalian transfection protocols.

[0241] In another embodiment of the invention, diseases or disorders caused by genetic defects with respect to SECP expression are treated by constructing a retrovirus vector consisting of (i) the polynucleotide encoding SECP under the control of an independent promoter or the retrovirus long terminal repeat (LTR) promoter, (ii) appropriate RNA packaging signals, and (iii) a Rev-responsive element (RRE) along with additional retrovirus cis-acting RNA sequences and coding sequences required for efficient vector propagation. Retrovirus vectors (e.g., PFB and PFBNEO) are commercially available (Stratagene) and are based on published data (Riviere, I. et al. (1995) Proc. Natl. Acad. Sci. USA 92:6733-6737), incorporated by reference herein. The vector is propagated in an appropriate vector producing cell line (VPCL) that expresses an envelope gene with a tropism for receptors on the target cells or a promiscuous envelope protein such as VSVg (Armentano, D. et al. (1987) J. Virol. 61:1647-1650; Bender, M. A. et al. (1987) J. Virol. 61:1639-1646; Adam, M. A. and A. D. Miller (1988) J. Virol. 62:3802-3806; Dull, T. et al. (1998) J. Virol. 72:8463-8471; Zufferey, R. et al. (1998) J. Virol. 72:9873-9880). U.S. Pat. No. 5,910,434 to Rigg (“Method for obtaining retrovirus packaging cell lines producing high transducing efficiency retroviral supernatant”) discloses a method for obtaining retrovirus packaging cell lines and is hereby incorporated by reference. Propagation of retrovirus vectors, transduction of a population of cells (e.g., CD4⁺ T-cells), and the return of transduced cells to a patient are procedures well known to persons skilled in the art of gene therapy and have been well documented (Ranga, U. et al. (1997) J. Virol. 71:7020-7029; Bauer, G. et al. (1997) Blood 89:2259-2267; Bonyhadi, M. L. (1997) J. Virol. 71:4707-4716; Ranga, U. et al. (1998) Proc. Natl. Acad. Sci. USA 95:1201-1206; Su, L. (1997) Blood 89:2283-2290).

[0242] In an embodiment, an adenovirus-based gene therapy delivery system is used to deliver polynucleotides encoding SECP to cells which have one or more genetic abnormalities with respect to the expression of SECP. The construction and packaging of adenovirus-based vectors are well known to those with ordinary skill in the art. Replication defective adenovirus vectors have proven to be versatile for importing genes encoding immunoregulatory proteins into intact islets in the pancreas (Csete, M. E. et al. (1995) Transplantation 27:263-268). Potentially useful adenoviral vectors are described in U.S. Pat. No. 5,707,618 to Armentano (“Adenovirus vectors for gene therapy”), hereby incorporated by reference. For adenoviral vectors, see also Antinozzi, P. A. et al. (1999; Annu. Rev. Nutr. 19:511-544) and Verma, I. M. and N. Somia (1997; Nature 18:389:239-242).

[0243] In another embodiment, a herpes-based, gene therapy delivery system is used to deliver polynucleotides encoding SECP to target cells which have one or more genetic abnormalities with respect to the expression of SECP. The use of herpes simplex virus (HSV)-based vectors may be especially valuable for introducing SECP to cells of the central nervous system, for which HSV has a tropism. The construction and packaging of herpes-based vectors are well known to those with ordinary skill in the art. A replication-competent herpes simplex virus (HSV) type 1-based vector has been used to deliver a reporter gene to the eyes of primates (Liu, X. et al. (1999) Exp. Eye Res. 169:385-395). The construction of a HSV-1 virus vector has also been disclosed in detail in U.S. Pat. No. 5,804,413 to DeLuca (“Herpes simplex virus strains for gene transfer”), which is hereby incorporated by reference. U.S. Pat. No. 5,804,413 teaches the use of recombinant HSV d92 which consists of a genome containing at least one exogenous gene to be transferred to a cell under the control of the appropriate promoter for purposes including human gene therapy. Also taught by this patent are the construction and use of recombinant HSV strains deleted for ICP4, ICP27 and ICP22. For HSV vectors, see also Goins, W. F. et al. (1999; J. Virol. 73:519-532) and Xu, H. et al. (1994; Dev. Biol. 163:152-161). The manipulation of cloned herpesvirus sequences, the generation of recombinant virus following the transfection of multiple plasmids containing different segments of the large herpesvirus genomes, the growth and propagation of herpesvirus, and the infection of cells with herpesvirus are techniques well known to those of ordinary skill in the art.

[0244] In another embodiment, an alphavirus (positive, single-stranded RNA virus) vector is used to deliver polynucleotides encoding SECP to target cells. The biology of the prototypic alphavirus, Semliki Forest Virus (SFV), has been studied extensively and gene transfer vectors have been based on the SFV genome (Garoff, H. and K.-J. Li (1998) Curr. Opin. Biotechnol. 9:464469). During alphavirus RNA replication, a subgenomic RNA is generated that normally encodes the viral capsid proteins. This subgenomic RNA replicates to higher levels than the full length genomic RNA, resulting in the overproduction of capsid proteins relative to the viral proteins with enzymatic activity (e.g., protease and polymerase). Similarly, inserting the coding sequence for SECP into the alphavirus genome in place of the capsid-coding region results in the production of a large number of SECP-coding RNAs and the synthesis of high levels of SECP in vector transduced cells. While alphavirus infection is typically associated with cell lysis within a few days, the ability to establish a persistent infection in hamster normal kidney cells (BHK-21) with a variant of Sindbis virus (SIN) indicates that the lytic replication of alphaviruses can be altered to suit the needs of the gene therapy application (Dryga, S. A. et al. (1997) Virology 228:74-83). The wide host range of alphaviruses will allow the introduction of SECP into a variety of cell types. The specific transduction of a subset of cells in a population may require the sorting of cells prior to transduction. The methods of manipulating infectious cDNA clones of alphaviruses, performing alphavirus cDNA and RNA transfections, and performing alphavirus infections, are well known to those with ordinary skill in the art.

[0245] Oligonucleotides derived from the transcription initiation site, e.g., between about positions −10 and +10 from the start site, may also be employed to inhibit gene expression. Similarly, inhibition can be achieved using triple helix base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or regulatory molecules. Recent therapeutic advances using triplex DNA have been described in the literature (Gee, J. E. et al. (1994) in Huber, B. E. and B. I. Carr, Molecular and Immunologic Approaches, Futura Publishing, Mt. Kisco N.Y., pp. 163-177). A complementary sequence or antisense molecule may also be designed to block translation of mRNA by preventing the transcript from binding to ribosomes.

[0246] Ribozymes, enzymatic RNA molecules, may also be used to catalyze the specific cleavage of RNA. The mechanism of ribozyme action involves sequence-specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage. For example, engineered hammerhead motif ribozyme molecules may specifically and efficiently catalyze endonucleolytic cleavage of RNA molecules encoding SECP.

[0247] Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, including the following sequences: GUA, GUU, and GUC. Once identified, short RNA sequences of between 15 and 20 ribonucleotides, corresponding to the region of the target gene containing the cleavage site, may be evaluated for secondary structural features which may render the oligonucleotide inoperable. The suitability of candidate targets may also be evaluated by testing accessibility to hybridization with complementary oligonucleotides using ribonuclease protection assays.

[0248] Complementary ribonucleic acid molecules and ribozymes may be prepared by any method known in the art for the synthesis of nucleic acid molecules. These include techniques for chemically synthesizing oligonucleotides such as solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA molecules encoding SECP. Such DNA sequences may be incorporated into a wide variety of vectors with suitable RNA polymerase promoters such as T7 or SP6. Alternatively, these cDNA constructs that synthesize complementary RNA, constitutively or inducibly, can be introduced into cell lines, cells, or tissues.

[0249] RNA molecules may be modified to increase intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5′ and/or 3′ ends of the molecule, or the use of phosphorothioate or 2′ O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept is inherent in the production of PNAs and can be extended in all of these molecules by the inclusion of nontraditional bases such as inosine, queosine, and wybutosine, as well as acetyl-, methyl-, thio-, and similarly modified forms of adenine, cytidine, guanine, thymine, and uridine which are not as easily recognized by endogenous endonucleases.

[0250] An additional embodiment of the invention encompasses a method for screening for a compound which is effective in altering expression of a polynucleotide encoding SECP. Compounds which may be effective in altering expression of a specific polynucleotide may include, but are not limited to, oligonucleotides, antisense oligonucleotides, triple helix-forming oligonucleotides, transcription factors and other polypeptide transcriptional regulators, and non-macromolecular chemical entities which are capable of interacting with specific polynucleotide sequences. Effective compounds may alter polynucleotide expression by acting as either inhibitors or promoters of polynucleotide expression. Thus, in the treatment of disorders associated with increased SECP expression or activity, a compound which specifically inhibits expression of the polynucleotide encoding SECP may be therapeutically useful, and in the treatment of disorders associated with decreased SECP expression or activity, a compound which specifically promotes expression of the polynucleotide encoding SECP may be therapeutically useful.

[0251] At least one, and up to a plurality, of test compounds may be screened for effectiveness in altering expression of a specific polynucleotide. A test compound may be obtained by any method commonly known in the art, including chemical modification of a compound known to be effective in altering polynucleotide expression; selection from an existing, commercially-available or proprietary library of naturally-occurring or non-natural chemical compounds; rational design of a compound based on chemical and/or structural properties of the target polynucleotide; and selection from a library of chemical compounds created combinatorially or randomly. A sample comprising a polynucleotide encoding SECP is exposed to at least one test compound thus obtained. The sample may comprise, for example, an intact or permeabilized cell, or an in vitro cell-free or reconstituted biochemical system. Alterations in the expression of a polynucleotide encoding SECP are assayed by any method commonly known in the art. Typically, the expression of a specific nucleotide is detected by hybridization with a probe having a nucleotide sequence complementary to the sequence of the polynucleotide encoding SECP. The amount of hybridization may be quantified, thus forming the basis for a comparison of the expression of the polynucleotide both with and without exposure to one or more test compounds. Detection of a change in the expression of a polynucleotide exposed to a test compound indicates that the test compound is effective in altering the expression of the polynucleotide. A screen for a compound effective in altering expression of a specific polynucleotide can be carried out, for example, using a Schizosaccharomyces pombe gene expression system (Atkins, D. et al. (1999) U.S. Pat. No. 5,932,435; Arndt, G. M. et al. (2000) Nucleic Acids Res. 28:E15) or a human cell line such as HeLa cell (Clarke, M. L. et al. (2000) Biochem. Biophys. Res. Commun. 268:8-13). A particular embodiment of the present invention involves screening a combinatorial library of oligonucleotides (such as deoxyribonucleotides, ribonucleotides, peptide nucleic acids, and modified oligonucleotides) for antisense activity against a specific polynucleotide sequence (Bruice, T. W. et al. (1997) U.S. Pat. No. 5,686,242; Bruice, T. W. et al. (2000) U.S. Pat. No. 6,022,691).

[0252] Many methods for introducing vectors into cells or tissues are available and equally suitable for use in vivo, in vitro, and ex vivo. For ex vivo therapy, vectors may be introduced into stem cells taken from the patient and clonally propagated for autologous transplant back into that same patient. Delivery by transfection, by liposome injections, or by polycationic amino polymers may be achieved using methods which are well known in the art (Goldman, C. K. et al. (1997) Nat. Biotechnol. 15:462-466).

[0253] Any of the therapeutic methods described above may be applied to any subject in need of such therapy, including, for example, mammals such as humans, dogs, cats, cows, horses, rabbits, and monkeys.

[0254] An additional embodiment of the invention relates to the administration of a composition which generally comprises an active ingredient formulated with a pharmaceutically acceptable excipient. Excipients may include, for example, sugars, starches, celluloses, gums, and proteins. Various formulations are commonly known and are thoroughly discussed in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing, Easton Pa.). Such compositions may consist of SECP, antibodies to SECP, and mimetics, agonists, antagonists, or inhibitors of SECP.

[0255] The compositions utilized in this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal means.

[0256] Compositions for pulmonary administration may be prepared in liquid or dry powder form. These compositions are generally aerosolized immediately prior to inhalation by the patient. In the case of small molecules (e.g. traditional low molecular weight organic drugs), aerosol delivery of fast-acting formulations is well-known in the art. In the case of macromolecules (e.g. larger peptides and proteins), recent developments in the field of pulmonary delivery via the alveolar region of the lung have enabled the practical delivery of drugs such as insulin to blood circulation (see, e.g., Patton, J. S. et al., U.S. Pat. No. 5,997,848). Pulmonary delivery has the advantage of administration without needle injection, and obviates the need for potentially toxic penetration enhancers.

[0257] Compositions suitable for use in the invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.

[0258] Specialized forms of compositions may be prepared for direct intracellular delivery of macromolecules comprising SECP or fragments thereof. For example, liposome preparations containing a cell-impermeable macromolecule may promote cell fusion and intracellular delivery of the macromolecule. Alternatively, SECP or a fragment thereof may be joined to a short cationic N-terminal portion from the HIV Tat-1 protein. Fusion proteins thus generated have been found to transduce into the cells of all tissues, including the brain, in a mouse model system (Schwarze, S. R. et al. (1999) Science 285:1569-1572).

[0259] For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models such as mice, rats, rabbits, dogs, monkeys, or pigs. An animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.

[0260] A therapeutically effective dose refers to that amount of active ingredient, for example SECP or fragments thereof, antibodies of SECP, and agonists, antagonists or inhibitors of SECP, which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals, such as by calculating the ED₅₀ (the dose therapeutically effective in 50% of the population) or LD₅₀ (the dose lethal to 50% of the population) statistics. The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the LD₅₀/ED₅₀ ratio. Compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies are used to formulate a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that includes the ED₅₀ with little or no toxicity. The dosage varies within this rarnge depending upon the dosage form employed, the sensitivity of the patient, and the route of administration.

[0261] The exact dosage will be determined by the practitioner, in light of factors related to the subject requiring treatment. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, the general health of the subject, the age, weight, and gender of the subject, time and frequency of administration, drug combination(s), reaction sensitivities, and response to therapy. Long-acting compositions may be administered every 3 to 4 days, every week, or biweekly depending on the half-life and clearance rate of the particular formulation.

[0262] Normal dosage amounts may vary from about 0.1 μg to 100,000 μg, up to a total dose of about 1 gram, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art. Those skilled in the art will employ different formulations for nucleotides than for proteins or their inhibitors. Similarly, delivery of polynucleotides or polypeptides will be specific to particular cells, conditions, locations, etc.

Diagnostics

[0263] In another embodiment, antibodies which specifically bind SECP may be used for the diagnosis of disorders characterized by expression of SECP, or in assays to monitor patients being treated with SECP or agonists, antagonists, or inhibitors of SECP. Antibodies useful for diagnostic purposes may be prepared in the same manner as described above for therapeutics. Diagnostic assays for SECP include methods which utilize the antibody and a label to detect SECP in human body fluids or in extracts of cells or tissues. The antibodies may be used with or without modification, and may be labeled by covalent or non-covalent attachment of a reporter molecule. A wide variety of reporter molecules, several of which are described above, are known in the art and may be used.

[0264] A variety of protocols for measuring SECP, including ELISAs, RIAs, and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of SECP expression. Normal or standard values for SECP expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, for example, human subjects, with antibodies to SECP under conditions suitable for complex formation. The amount of standard complex formation may be quantitated by various methods, such as photometric means. Quantities of SECP expressed in subject, control, and disease samples from biopsied tissues are compared with the standard values. Deviation between standard and subject values establishes the parameters for diagnosing disease.

[0265] In another embodiment of the invention, polynucleotides encoding SECP may be used for diagnostic purposes. The polynucleotides which may be used include oligonucleotides, complementary RNA and DNA molecules, and PNAs. The polynucleotides may be used to detect and quantify gene expression in biopsied tissues in which expression of SECP may be correlated with disease. The diagnostic assay may be used to determine absence, presence, and excess expression of SECP, and to monitor regulation of SECP levels during therapeutic intervention.

[0266] In one aspect, hybridization with PCR probes which are capable of detecting polynucleotides, including genomic sequences, encoding SECP or closely related molecules may be used to identify nucleic acid sequences which encode SECP. The specificity of the probe, whether it is made from a highly specific region, e.g., the 5′ regulatory region, or from a less specific region, e.g., a conserved motif, and the stringency of the hybridization or amplification will determine whether the probe identifies only naturally occurring sequences encoding SECP, allelic variants, or related sequences.

[0267] Probes may also be used for the detection of related sequences, and may have at least 50% sequence identity to any of the SECP encoding sequences. The hybridization probes of the subject invention may be DNA or RNA and may be derived from the sequence of SEQ ID NO:32-62 or from genomic sequences including promoters, enhancers, and introns of the SECP gene.

[0268] Means for producing specific hybridization probes for polynucleotides encoding SECP include the cloning of polynucleotides encoding SECP or SECP derivatives into vectors for the production of mRNA probes. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA polymerases and the appropriate labeled nucleotides. Hybridization probes may be labeled by a variety of reporter groups, for example, by radionuclides such as ³²P or ³⁵S, or by enzymatic labels, such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems, and the like.

[0269] Polynucleotides encoding SECP may be used for the diagnosis of disorders associated with expression of SECP. Examples of such disorders include, but are not limited to, a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, a cancer of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus; an autoimmune/inflammatory disorder such as acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, and trauma; a cardiovascular disorder such as congestive heart failure, ischemic heart disease, angina pectoris, myocardial infarction, hypertensive heart disease, degenerative valvular heart disease, calcific aortic valve stenosis, congenitally bicuspid aortic valve, mitral annular calcification, mitral valve prolapse, rheumatic fever and rheumatic heart disease, infective endocarditis, nonbacterial thrombotic endocarditis, endocarditis of systemic lupus erythematosus, carcinoid heart disease, cardiomyopathy, myocarditis, pericarditis, neoplastic heart disease, congenital heart disease, complications of cardiac transplantation, arteriovenous fistula, atherosclerosis, hypertension, vasculitis, Raynaud's disease, aneurysms, arterial dissections, varicose veins, thrombophlebitis and phlebothrombosis, vascular tumors, and complications of thrombolysis, balloon angioplasty, vascular replacement, and coronary artery bypass graft surgery; a neurological disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, prion diseases including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorders of the central nervous system including Down syndrome, cerebral palsy, neuroskeletal disorders, autonomic nervous system disorders, cranial nerve disorders, spinal cord diseases, muscular dystrophy and other neuromuscular disorders, peripheral nervous system disorders, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis, mental disorders including mood, anxiety, and schizophrenic disorders, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, Tourette's disorder, progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia; and a developmental disorder such as renal tubular acidosis, anemia, Cushing's syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, epilepsy, gonadal dysgenesis, WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas, hereditary neuropathies such as Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as Syndenham's chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, and sensorineural hearing loss. Polynucleotides encoding SECP may be used in Southern or northern analysis, dot blot, or other membrane-based technologies; in PCR technologies; in dipstick, pin, and multiformat ELISA-like assays; and in microarrays utilizing fluids or tissues from patients to detect altered SECP expression. Such qualitative or quantitative methods are well known in the art.

[0270] In a particular aspect, polynucleotides encoding SECP may be used in assays that detect the presence of associated disorders, particularly those mentioned above. Polynucleotides complementary to sequences encoding SECP may be labeled by standard methods and added to a fluid or tissue sample from a patient under conditions suitable for the formation of hybridization complexes. After a suitable incubation period, the sample is washed and the signal is quantified and compared with a standard value. If the amount of signal in the patient sample is significantly altered in comparison to a control sample then the presence of altered levels of polynucleotides encoding SECP in the sample indicates the presence of the associated disorder. Such assays may also be used to evaluate the efficacy of a particular therapeutic treatment regimen in animal studies, in clinical trials, or to monitor the treatment of an individual patient.

[0271] In order to provide a basis for the diagnosis of a disorder associated with expression of SECP, a normal or standard profile for expression is established. This may be accomplished by combining body fluids or cell extracts taken from normal subjects, either animal or human, with a sequence, or a fragment thereof, encoding SECP, under conditions suitable for hybridization or amplification. Standard hybridization may be quantified by comparing the values obtained from normal subjects with values from an experiment in which a known amount of a substantially purified polynucleotide is used. Standard values obtained in this manner may be compared with values obtained from samples from patients who are symptomatic for a disorder. Deviation from standard values is used to establish the presence of a disorder.

[0272] Once the presence of a disorder is established and a treatment protocol is initiated, hybridization assays may be repeated on a regular basis to determine if the level of expression in the patient begins to approximate that which is observed in the normal subject. The results obtained from successive assays may be used to show the efficacy of treatment over a period ranging from several days to months.

[0273] With respect to cancer, the presence of an abnormal amount of transcript (either under- or overexpressed) in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier, thereby preventing the development or further progression of the cancer.

[0274] Additional diagnostic uses for oligonucleotides designed from the sequences encoding SECP may involve the use of PCR. These oligomers may be chemically synthesized, generated enzymatically, or produced in vitro. Oligomers will preferably contain a fragment of a polynucleotide encoding SECP, or a fragment of a polynucleotide complementary to the polynucleotide encoding SECP, and will be employed under optimized conditions for identification of a specific gene or condition. Oligomers may also be employed under less stringent conditions for detection or quantification of closely related DNA or RNA sequences.

[0275] In a particular aspect, oligonucleotide primers derived from polynucleotides encoding SECP may be used to detect single nucleotide polymorphisms (SNPs). SNPs are substitutions, insertions and deletions that are a frequent cause of inherited or acquired genetic disease in humans. Methods of SNP detection include, but are not limited to, single-stranded conformation polymorphism (SSCP) and fluorescent SSCP (fSSCP) methods. In SSCP, oligonucleotide primers derived from polynucleotides encoding SECP are used to amplify DNA using the polymerase chain reaction (PCR). The DNA may be derived, for example, from diseased or normal tissue, biopsy samples, bodily fluids, and the like. SNPs in the DNA cause differences in the secondary and tertiary structures of PCR products in single-stranded form, and these differences are detectable using gel electrophoresis in non-denaturing gels. In fSCCP, the oligonucleotide primers are fluorescently labeled, which allows detection of the amplimers in high-throughput equipment such as DNA sequencing machines. Additionally, sequence database analysis methods, termed in silico SNP (isSNP), are capable of identifying polymorphisms by comparing the sequence of individual overlapping DNA fragments which assemble into a common consensus sequence. These computer-based methods filter out sequence variations due to laboratory preparation of DNA and sequencing errors using statistical models and automated analyses of DNA sequence chromatograms. In the alternative, SNPs may be detected and characterized by mass spectrometry using, for example, the high throughput MASSARRAY system (Sequenom, Inc., San Diego Calif.).

[0276] SNPs may be used to study the genetic basis of human disease. For example, at least 16 common SNPs have been associated with non-insulin-dependent diabetes mellitus. SNPs are also useful for examining differences in disease outcomes in monogenic disorders, such as cystic fibrosis, sickle cell anemia, or chronic granulomatous disease. For example, variants in the mannose-binding lectin, MBL2, have been shown to be correlated with deleterious pulmonary outcomes in cystic fibrosis. SNPs also have utility in pharmacogenomics, the identification of genetic variants that influence a patient's response to a drug, such as life-threatening toxicity. For example, a variation in N-acetyl transferase is associated with a high incidence of peripheral neuropathy in response to the anti-tuberculosis drug isoniazid, while a variation in the core promoter of the ALOX5 gene results in diminished clinical response to treatment with an anti-asthma drug that targets the 5-lipoxygenase pathway. Analysis of the distribution of SNPs in different populations is useful for investigating genetic drift, mutation, recombination, and selection, as well as for tracing the origins of populations and their migrations (Taylor, J. G. et al. (2001) Trends Mol. Med. 7:507-512; Kwok, P.-Y. and Z. Gu (1999) Mol. Med. Today 5:538-543; Nowotny, P. et al. (2001) Curr. Opin. Neurobiol. 11:637-641).

[0277] Methods which may also be used to quantify the expression of SECP include radiolabeling or biotinylating nucleotides, coamplification of a control nucleic acid, and interpolating results from standard curves (Melby, P. C. et al. (1993) J. Immunol. Methods 159:235-244; Duplaa, C. et al. (1993) Anal. Biochem. 212:229-236). The speed of quantitation of multiple samples may be accelerated by running the assay in a high-throughput format where the oligomer or polynucleotide of interest is presented in various dilutions and a spectrophotometric or colorimetric response gives rapid quantitation.

[0278] In further embodiments, oligonucleotides or longer fragments derived from any of the polynucleotides described herein may be used as elements on a microarray. The microarray can be used in transcript imaging techniques which monitor the relative expression levels of large numbers of genes simultaneously as described below. The microarray may also be used to identify genetic variants, mutations, and polymorphisms. This information may be used to determine gene function, to understand the genetic basis of a disorder, to diagnose a disorder, to monitor progression/regression of disease as a function of gene expression, and to develop and monitor the activities of therapeutic agents in the treatment of disease. In particular, this information may be used to develop a pharmacogenomic profile of a patient in order to select the most appropriate and effective treatment regimen for that patient. For example, therapeutic agents which are highly effective and display the fewest side effects may be selected for a patient based on his/her pharmacogenomic profile.

[0279] In another embodiment, SECP, fragments of SECP, or antibodies specific for SECP may be used as elements on a microarray. The microarray may be used to monitor or measure protein-protein interactions, drug-target interactions, and gene expression profiles, as described above.

[0280] A particular embodiment relates to the use of the polynucleotides of the present invention to generate a transcript image of a tissue or cell type. A transcript image represents the global pattern of gene expression by a particular tissue or cell type. Global gene expression patterns are analyzed by quantifying the number of expressed genes and their relative abundance under given conditions and at a given time (Seilhamer et al., “Comparative Gene Transcript Analysis,” U.S. Pat. No. 5,840,484; hereby expressly incorporated by reference herein). Thus a transcript image may be generated by hybridizing the polynucleotides of the present invention or their complements to the totality of transcripts or reverse transcripts of a particular tissue or cell type. In one embodiment, the hybridization takes place in high-throughput format, wherein the polynucleotides of the present invention or their complements comprise a subset of a plurality of elements on a microarray. The resultant transcript image would provide a profile of gene activity.

[0281] Transcript images may be generated using transcripts isolated from tissues, cell lines, biopsies, or other biological samples. The transcript image may thus reflect gene expression in vivo, as in the case of a tissue or biopsy sample, or in vitro, as in the case of a cell line.

[0282] Transcript images which profile the expression of the polynucleotides of the present invention may also be used in conjunction with in vitro model systems and preclinical evaluation of pharmaceuticals, as well as toxicological testing of industrial and naturally-occurring environmental compounds. All compounds induce characteristic gene expression patterns, frequently termed molecular fingerprints or toxicant signatures, which are indicative of mechanisms of action and toxicity (Nuwaysir, E. F. et al. (1999) Mol. Carcinog. 24:153-159; Steiner, S. and N. L. Anderson (2000) Toxicol. Lett. 112-113:467-471). If a test compound has a signature similar to that of a compound with known toxicity, it is likely to share those toxic properties. These fingerprints or signatures are most useful and refined when they contain expression information from a large number of genes and gene families. Ideally, a genome-wide measurement of expression provides the highest quality signature. Even genes whose expression is not altered by any tested compounds are important as well, as the levels of expression of these genes are used to normalize the rest of the expression data. The normalization procedure is useful for comparison of expression data after treatment with different compounds. While the assignment of gene function to elements of a toxicant signature aids in interpretation of toxicity mechanisms, knowledge of gene function is not necessary for the statistical matching of signatures which leads to prediction of toxicity (see, for example, Press Release 00-02 from the National Institute of Environmental Health Sciences, released Feb. 29, 2000, available at http://www.niehs.nih.gov/oc/news/toxchip.htm). Therefore, it is important and desirable in toxicological screening using toxicant signatures to include all expressed gene sequences.

[0283] In an embodiment, the toxicity of a test compound can be assessed by treating a biological sample containing nucleic acids with the test compound. Nucleic acids that are expressed in the treated biological sample are hybridized with one or more probes specific to the polynucleotides of the present invention, so that transcript levels corresponding to the polynucleotides of the present invention may be quantified. The transcript levels in the treated biological sample are compared with levels in an untreated biological sample. Differences in the transcript levels between the two samples are indicative of a toxic response caused by the test compound in the treated sample.

[0284] Another embodiment relates to the use of the polypeptides disclosed herein to analyze the proteome of a tissue or cell type. The term proteome refers to the global pattern of protein expression in a particular tissue or cell type. Each protein component of a proteome can be subjected individually to further analysis. Proteome expression patterns, or profiles, are analyzed by quantifying the number of expressed proteins and their relative abundance under given conditions and at a given time. A profile of a cell's proteome may thus be generated by separating and analyzing the polypeptides of a particular tissue or cell type. In one embodiment, the separation is achieved using two-dimensional gel electrophoresis, in which proteins from a sample are separated by isoelectric focusing in the first dimension, and then according to molecular weight by sodium dodecyl sulfate slab gel electrophoresis in the second dimension (Steiner and Anderson, supra). The proteins are visualized in the gel as discrete and uniquely positioned spots, typically by staining the gel with an agent such as Coomassie Blue or silver or fluorescent stains. The optical density of each protein spot is generally proportional to the level of the protein in the sample. The optical densities of equivalently positioned protein spots from different samples, for example, from biological samples either treated or untreated with a test compound or therapeutic agent, are compared to identify any changes in protein spot density related to the treatment. The proteins in the spots are partially sequenced using, for example, standard methods employing chemical or enzymatic cleavage followed by mass spectrometry. The identity of the protein in a spot may be determined by comparing its partial sequence, preferably of at least 5 contiguous amino acid residues, to the polypeptide sequences of interest. In some cases, further sequence data may be obtained for definitive protein identification.

[0285] A proteomic profile may also be generated using antibodies specific for SECP to quantify the levels of SECP expression. In one embodiment, the antibodies are used as elements on a microarray, and protein expression levels are quantified by exposing the microarray to the sample and detecting the levels of protein bound to each array element (Lueking, A. et al. (1999) Anal. Biochem. 270:103-111; Mendoze, L. G. et al. (1999) Biotechniques 27:778-788). Detection may be performed by a variety of methods known in the art, for example, by reacting the proteins in the sample with a thiol- or amino-reactive fluorescent compound and detecting the amount of fluorescence bound at each array element.

[0286] Toxicant signatures at the proteome level are also useful for toxicological screening, and should be analyzed in parallel with toxicant signatures at the transcript level. There is a poor correlation between transcript and protein abundances for some proteins in some tissues (Anderson, N. L. and J. Seilhamer (1997) Electrophoresis 18:533-537), so proteome toxicant signatures may be useful in the analysis of compounds which do not significantly affect the transcript image, but which alter the proteomic profile. In addition, the analysis of transcripts in body fluids is difficult, due to rapid degradation of mRNA, so proteomic profiling may be more reliable and informative in such cases.

[0287] In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins that are expressed in the treated biological sample are separated so that the amount of each protein can be quantified. The amount of each protein is compared to the amount of the corresponding protein in an untreated biological sample. A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample. Individual proteins are identified by sequencing the amino acid residues of the individual proteins and comparing these partial sequences to the polypeptides of the present invention.

[0288] In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins from the biological sample are incubated with antibodies specific to the polypeptides of the present invention. The amount of protein recognized by the antibodies is quantified. The amount of protein in the treated biological sample is compared with the amount in an untreated biological sample. A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample.

[0289] Microarrays may be prepared, used, and analyzed using methods known in the art (Brennan, T. M. et al. (1995) U.S. Pat. No. 5,474,796; Schena, M. et al. (1996) Proc. Natl. Acad. Sci. USA 93:10614-10619; Baldeschweiler et al. (1995) PCT application WO95/251116; Shalon, D. et al. (1995) PCT application WO95/35505; Heller, R. A. et al. (1997) Proc. Natl. Acad. Sci. USA 94:2150-2155; Heller, M. J. et al. (1997) U.S. Pat. No. 5,605,662). Various types of microarrays are well known and thoroughly described in Schena, M., ed. (1999; DNA Microarrays: A Practical Approach, Oxford University Press, London).

[0290] In another embodiment of the invention, nucleic acid sequences encoding SECP may be used to generate hybridization probes useful in mapping the naturally occurring genomic sequence. Either coding or noncoding sequences may be used, and in some instances, noncoding sequences may be preferable over coding sequences. For example, conservation of a coding sequence among members of a multi-gene family may potentially cause undesired cross hybridization during chromosomal mapping. The sequences may be mapped to a particular chromosome, to a specific region of a chromosome, or to artificial chromosome constructions, e.g., human artificial chromosomes (HACs), yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), bacterial P1 constructions, or single chromosome cDNA libraries (Harrington, J. J. et al. (1997) Nat. Genet. 15:345-355; Price, C. M. (1993) Blood Rev. 7:127-134; Trask, B. J. (1991) Trends Genet. 7:149-154). Once mapped, the nucleic acid sequences may be used to develop genetic linkage maps, for example, which correlate the inheritance of a disease state with the inheritance of a particular chromosome region or restriction fragment length polymorphism (RFLP) (Lander, E. S. and D. Botstein (1986) Proc. Natl. Acad. Sci. USA 83:7353-7357).

[0291] Fluorescent in situ hybridization (FISH) may be correlated with other physical and genetic map data (Heinz-Ulrich, et al. (1995) in Meyers, supra, pp. 965-968). Examples of genetic map data can be found in various scientific journals or at the Online Mendelian Inheritance in Man (OMIM) World Wide Web site. Correlation between the location of the gene encoding SECP on a physical map and a specific disorder, or a predisposition to a specific disorder, may help define the region of DNA associated with that disorder and thus may further positional cloning efforts.

[0292] In situ hybridization of chromosomal preparations and physical mapping techniques, such as linkage analysis using established chromosomal markers, may be used for extending genetic maps. Often the placement of a gene on the chromosome of another mammalian species, such as mouse, may reveal associated markers even if the exact chromosomal locus is not known. This information is valuable to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the gene or genes responsible for a disease or syndrome have been crudely localized by genetic linkage to a particular genomic region, e.g., ataxia-telangiectasia to 1 q22-23, any sequences mapping to that area may represent associated or regulatory genes for further investigation (Gatti, R. A. et al. (1988) Nature 336:577-580). The nucleotide sequence of the instant invention may also be used to detect differences in the chromosomal location due to translocation, inversion, etc., among normal, carrier, or affected individuals.

[0293] In another embodiment of the invention, SECP, its catalytic or immunogenic fragments, or oligopeptides thereof can be used for screening libraries of compounds in any of a variety of drug screening techniques. The fragment employed in such screening may be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. The formation of binding complexes between SECP and the agent being tested may be measured.

[0294] Another technique for drug screening provides for high throughput screening of compounds having suitable binding affinity to the protein of interest (Geysen, et al. (1984) PCT application WO84/03564). In this method, large numbers of different small test compounds are synthesized on a solid substrate. The test compounds are reacted with SECP, or fragments thereof, and washed. Bound SECP is then detected by methods well known in the art. Purified SECP can also be coated directly onto plates for use in the aforementioned drug screening techniques. Alternatively, non-neutralizing antibodies can be used to capture the peptide and immobilize it on a solid support.

[0295] In another embodiment, one may use competitive drug screening assays in which neutralizing antibodies capable of binding SECP specifically compete with a test compound for binding SECP. In this manner, antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with SECP.

[0296] In additional embodiments, the nucleotide sequences which encode SECP may be used in any molecular biology techniques that have yet to be developed, provided the new techniques rely on properties of nucleotide sequences that are currently known, including, but not limited to, such properties as the triplet genetic code and specific base pair interactions.

[0297] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0298] The disclosures of all patents, applications and publications, mentioned above and below, are expressly incorporated by reference herein. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0299] The disclosures of all patents, applications, and publications mentioned above and below, including U.S. Ser. No. 60/303,500, U.S. Ser. No. 60/305,403, U.S. Ser. No. 60/307,011, U.S. Ser. No. 60,308,187, U.S. Ser. No. 60/309,416, U.S. Ser. No. 60/311,740, and U.S. Ser. No. 60/343,553 are hereby expressly incorporated by reference.

EXAMPLES

[0300] I. Construction of cDNA Libraries

[0301] Incyte cDNAs were derived from cDNA libraries described in the LIFESEQ GOLD database (Incyte Genomics, Palo Alto Calif.). Some tissues were homogenized and lysed in guanidinium isothiocyanate, while others were homogenized and lysed in phenol or in a suitable mixture of denaturants, such as TRIZOL (Invitrogen), a monophasic solution of phenol and guanidine isothiocyanate. The resulting lysates were centrifuged over CsCl cushions or extracted with chloroform. RNA was precipitated from the lysates with either isopropanol or sodium acetate and ethanol, or by other routine methods.

[0302] Phenol extraction and precipitation of RNA were repeated as necessary to increase RNA purity. In some cases, RNA was treated with DNase. For most libraries, poly(A)+ RNA was isolated using oligo d(T)-coupled paramagnetic particles (Promega), OLIGOTEX latex particles (QIAGEN, Chatsworth Calif.), or an OLIGOTEX mRNA purification kit (QIAGEN). Alternatively, RNA was isolated directly from tissue lysates using other RNA isolation kits, e.g., the POLY(A)PURE mRNA purification kit (Ambion, Austin Tex.).

[0303] In some cases, Stratagene was provided with RNA and constructed the corresponding cDNA libraries. Otherwise, cDNA was synthesized and cDNA libraries were constructed with the UNIZAP vector system (Stratagene) or SUPERSCRIPT plasmid system (Invitrogen), using the recommended procedures or similar methods known in the art (Ausubel et al., supra, ch. 5). Reverse transcription was initiated using oligo d(T) or random primers. Synthetic oligonucleotide adapters were ligated to double stranded cDNA, and the cDNA was digested with the appropriate restriction enzyme or enzymes. For most libraries, the cDNA was size-selected (300-1000 bp) using SEPHACRYL S1000, SEPHAROSE CL2B, or SEPHAROSE CL4B column chromatography (Amersham Biosciences) or preparative agarose gel electrophoresis. cDNAs were ligated into compatible restriction enzyme sites of the polylinker of a suitable plasmid, e.g., PBLUESCRIPT plasmid (Stratagene), PSPORT1 plasmid (Invitrogen), PCDNA2.1 plasmid (Invitrogen, Carlsbad Calif.), PBK-CMV plasmid (Stratagene), PCR2-TOPOTA plasmid (Invitrogen), PCMV-ICIS plasmid (Stratagene), pIGEN (Incyte Genomics, Palo Alto Calif.), pRARE (Incyte Genomics), or pINCY (Incyte Genomics), or derivatives thereof. Recombinant plasmids were transformed into competent E. coli cells including XL1-Blue, XL1-BlueMRF, or SOLR from Stratagene or DH5α, DH10B, or ElectroMAX DH10B from Invitrogen.

[0304] II. Isolation of cDNA Clones

[0305] Plasmids obtained as described in Example I were recovered from host cells by in vivo excision using the UNIZAP vector system (Stratagene) or by cell lysis. Plasmids were purified using at least one of the following: a Magic or WIZARD Minipreps DNA purification system (Promega); an AGTC Miniprep purification kit (Edge Biosystems, Gaithersburg Md.); and QIAWELL 8 Plasmid, QIAWELL 8 Plus Plasmid, QIAWELL 8 Ultra Plasmid purification systems or the R.E.A.L. PREP 96 plasmid purification kit from QIAGEN. Following precipitation, plasmids were resuspended in 0.1 ml of distilled water and stored, with or without lyophilization, at 4° C.

[0306] Alternatively, plasmid DNA was amplified from host cell lysates using direct link PCR in a high-throughput format (Rao, V. B. (1994) Anal. Biochem. 216:1-14). Host cell lysis and thermal cycling steps were carried out in a single reaction mixture. Samples were processed and stored in 384-well plates, and the concentration of amplified plasmid DNA was quantified fluorometrically using PICOGREEN dye (Molecular Probes, Eugene Oreg.) and a FLUOROSKAN II fluorescence scanner (Labsystems Oy, Helsinki, Finland).

[0307] III. Sequencing and Analysis

[0308] Incyte cDNA recovered in plasmids as described in Example II were sequenced as follows. Sequencing reactions were processed using standard methods or high-throughput instrumentation such as the ABI CATALYST 800 (Applied Biosystems) thermal cycler or the PTC-200 thermal cycler (MJ Research) in conjunction with the HYDRA microdispenser (Robbins Scientific) or the MICROLAB 2200 (Hamilton) liquid transfer system. cDNA sequencing reactions were prepared using reagents provided by Amersham Biosciences or supplied in ABI sequencing kits such as the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems). Electrophoretic separation of cDNA sequencing reactions and detection of labeled polynucleotides were carried out using the MEGABACE 1000 DNA sequencing system (Amersham Biosciences); the ABI PRISM 373 or 377 sequencing system (Applied Biosystems) in conjunction with standard ABI protocols and base calling software; or other sequence analysis systems known in the art. Reading frames within the cDNA sequences were identified using standard methods (Ausubel et al., supra, ch. 7). Some of the cDNA sequences were selected for extension using the techniques disclosed in Example VIII.

[0309] The polynucleotide sequences derived from Incyte cDNAs were validated by removing vector, linker, and poly(A) sequences and by masking ambiguous bases, using algorithms and programs based on BLAST, dynamic programming, and dinucleotide nearest neighbor analysis. The Incyte cDNA sequences or translations thereof were then queried against a selection of public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases, and BLOCKS, PRINTS, DOMO, PRODOM; PROTEOME databases with sequences from Homo sapiens, Rattus norvegicus, Mus musculus, Caenorhabditis elegans, Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Candida albicans (Incyte Genomics, Palo Alto Calif.); hidden Markov model (HMM)-based protein family databases such as PFAM, INCY, and TIGRFAM (Haft, D. H. et al. (2001) Nucleic Acids Res. 29:41-43); and HMM-based protein domain databases such as SMART (Schultz, J. et al. (1998) Proc. Natl. Acad. Sci. USA 95:5857-5864; Letunic, I. et al. (2002) Nucleic Acids Res. 30:242-244). (HMM is a probabilistic approach which analyzes consensus primary structures of gene families; see, for example, Eddy, S. R. (1996) Curr. Opin. Struct. Biol. 6:361-365.) The queries were performed using programs based on BLAST, FASTA, BLIMPS, and HMMER. The Incyte cDNA sequences were assembled to produce full length polynucleotide sequences. Alternatively, GenBank cDNAs, GenBank ESTs, stitched sequences, stretched sequences, or Genscan-predicted coding sequences (see Examples IV and V) were used to extend Incyte cDNA assemblages to full length. Assembly was performed using programs based on Phred, Phrap, and Consed, and cDNA assemblages were screened for open reading frames using programs based on GeneMark, BLAST, and FASTA. The full length polynucleotide sequences were translated to derive the corresponding full length polypeptide sequences. Alternatively, a polypeptide may begin at any of the methionine residues of the full length translated polypeptide. Full length polypeptide sequences were subsequently analyzed by querying against databases such as the GenBank protein databases (genpept), SwissProt, the PROTEOME databases, BLOCKS, PRINTS, DOMO, PRODOM, Prosite, hidden Markov model (HMM)-based protein family databases such as PFAM, INCY, and TIGRFAM; and HMM-based protein domain databases such as SMART. Full length polynucleotide sequences are also analyzed using MACDNASIS PRO software (Hitachi Software Engineering, South San Francisco Calif.) and LASERGENE software (DNASTAR). Polynucleotide and polypeptide sequence alignments are generated using default parameters specified by the CLUSTAL algorithm as incorporated into the MEGALIGN multisequence alignment program (DNASTAR), which also calculates the percent identity between aligned sequences.

[0310] Table 7 summarizes the tools, programs, and algorithms used for the analysis and assembly of Incyte cDNA and full length sequences and provides applicable descriptions, references, and threshold parameters. The first column of Table 7 shows the tools, programs, and algorithms used, the second column provides brief descriptions thereof, the third column presents appropriate references, all of which are incorporated by reference herein in their entirety, and the fourth column presents, where applicable, the scores, probability values, and other parameters used to evaluate the strength of a match between two sequences (the higher the score or the lower the probability value, the greater the identity between two sequences).

[0311] The programs described above for the assembly and analysis of full length polynucleotide and polypeptide sequences were also used to identify polynucleotide sequence fragments from SEQ ID NO:32-62. Fragments from about 20 to about 4000 nucleotides which are useful in hybridization and amplification technologies are described in Table 4, column 2.

[0312] IV. Identification and Editing of Coding Sequences from Genomic DNA

[0313] Putative secreted proteins were initially identified by running the Genscan gene identification program against public genomic sequence databases (e.g., gbpri and gbhtg). Genscan is a general-purpose gene identification program which analyzes genomic DNA sequences from a variety of organisms (Burge, C. and S. Karlin (1997) J. Mol. Biol. 268:78-94; Burge, C. and S. Karlin (1998) Curr. Opin. Struct. Biol. 8:346-354). The program concatenates predicted exons to form an assembled cDNA sequence extending from a methionine to a stop codon. The output of Genscan is a FASTA database of polynucleotide and polypeptide sequences. The maximum range of sequence for Genscan to analyze at once was set to 30 kb. To determine which of these Genscan predicted cDNA sequences encode secreted proteins, the encoded polypeptides were analyzed by querying against PFAM models for secreted proteins. Potential secreted proteins were also identified by homology to Incyte cDNA sequences that had been annotated as secreted proteins. These selected Genscan-predicted sequences were then compared by BLAST analysis to the genpept and gbpri public databases. Where necessary, the Genscan-predicted sequences were then edited by comparison to the top BLAST hit from genpept to correct errors in the sequence predicted by Genscan, such as extra or omitted exons. BLAST analysis was also used to find any Incyte cDNA or public cDNA coverage of the Genscan-predicted sequences, thus providing evidence for transcription. When Incyte cDNA coverage was available, this information was used to correct or confirm the Genscan predicted sequence. Full length polynucleotide sequences were obtained by assembling Genscan-predicted coding sequences with Incyte cDNA sequences and/or public cDNA sequences using the assembly process described in Example III. Alternatively, full length polynucleotide sequences were derived entirely from edited or unedited Genscan-predicted coding sequences.

[0314] V. Assembly of Genomic Sequence Data with cDNA Sequence Data

[0315] “Stitched” Sequences

[0316] Partial cDNA sequences were extended with exons predicted by the Genscan gene identification program described in Example IV. Partial cDNAs assembled as described in Example III were mapped to genomic DNA and parsed into clusters containing related cDNAs and Genscan exon predictions from one or more genomic sequences. Each cluster was analyzed using an algorithm based on graph theory and dynamic programming to integrate cDNA and genomic information, generating possible splice variants that were subsequently confirmed, edited, or extended to create a full length sequence. Sequence intervals in which the entire length of the interval was present on more than one sequence in the cluster were identified, and intervals thus identified were considered to be equivalent by transitivity. For example, if an interval was present on a cDNA and two genomic sequences, then all three intervals were considered to be equivalent. This process allows unrelated but consecutive genomic sequences to be brought together, bridged by cDNA sequence. Intervals thus identified were then “stitched” together by the stitching algorithm in the order that they appear along their parent sequences to generate the longest possible sequence, as well as sequence variants. Linkages between intervals which proceed along one type of parent sequence (cDNA to cDNA or genomic sequence to genomic sequence) were given preference over linkages which change parent type (cDNA to genomic sequence). The resultant stitched sequences were translated and compared by BLAST analysis to the genpept and gbpri public databases. Incorrect exons predicted by Genscan were corrected by comparison to the top BLAST hit from genpept. Sequences were further extended with additional cDNA sequences, or by inspection of genomic DNA, when necessary.

[0317] “Stretched” Sequences

[0318] Partial DNA sequences were extended to full length with an algorithm based on BLAST analysis. First, partial cDNAs assembled as described in Example III were queried against public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases using the BLAST program. The nearest GenBank protein homolog was then compared by BLAST analysis to either Incyte cDNA sequences or GenScan exon predicted sequences described in Example IV. A chimeric protein was generated by using the resultant high-scoring segment pairs (HSPs) to map the translated sequences onto the GenBank protein homolog. Insertions or deletions may occur in the chimeric protein with respect to the original GenBank protein homolog. The GenBank protein homolog, the chimeric protein, or both were used as probes to search for homologous genomic sequences from the public human genome databases. Partial DNA sequences were therefore “stretched” or extended by the addition of homologous genomic sequences. The resultant stretched sequences were examined to determine whether it contained a complete gene.

[0319] VI. Chromosomal Mapping of SECP Encoding Polynucleotides

[0320] The sequences which were used to assemble SEQ ID NO:32-62 were compared with sequences from the Incyte LIFESEQ database and public domain databases using BLAST and other implementations of the Smith-Waterman algorithm. Sequences from these databases that matched SEQ ID NO:32-62 were assembled into clusters of contiguous and overlapping sequences using assembly algorithms such as Phrap (Table 7). Radiation hybrid and genetic mapping data available from public resources such as the Stanford Human Genome Center (SHGC), Whitehead Institute for Genome Research (WIGR), and Généthon were used to determine if any of the clustered sequences had been previously mapped. Inclusion of a mapped sequence in a cluster resulted in the assignment of all sequences of that cluster, including its particular SEQ ID NO: to that map location.

[0321] Map locations are represented by ranges, or intervals, of human chromosomes. The map position of an interval, in centiMorgans, is measured relative to the terminus of the chromosome's p-arm. (The centiMorgan (cM) is a unit of measurement based on recombination frequencies between chromosomal markers. On average, 1 cM is roughly equivalent to 1 megabase (Mb) of DNA in humans, although this can vary widely due to hot and cold spots of recombination.) The cM distances are based on genetic markers mapped by Généthon which provide boundaries for radiation hybrid markers whose sequences were included in each of the clusters. Human genome maps and other resources available to the public, such as the NCBI “GeneMap'99” World Wide Web site (http://www.ncbi.nlm.nih.gov/genemap/), can be employed to determine if previously identified disease genes map within or in proximity to the intervals indicated above.

[0322] VII. Analysis of Polynucleotide Expression

[0323] Northern analysis is a laboratory technique used to detect the presence of a transcript of a gene and involves the hybridization of a labeled nucleotide sequence to a membrane on which RNAs from a particular cell type or tissue have been bound (Sambrook, supra, ch. 7; Ausubel et al., supra, ch. 4).

[0324] Analogous computer techniques applying BLAST were used to search for identical or related molecules in cDNA databases such as GenBank or LIFESEQ (Incyte Genomics). This analysis is much faster than multiple membrane-based hybridizations. In addition, the sensitivity of the computer search can be modified to determine whether any particular match is categorized as exact or similar. The basis of the search is the product score, which is defined as: $\frac{{BLAST}\quad {Score} \times {Percent}\quad {Identity}}{5 \times {minimum}\left\{ {{{length}\left( {{Seq}.\quad 1} \right)},{{length}\left( {{Seq}.\quad 2} \right)}} \right\}}$

[0325] The product score takes into account both the degree of similarity between two sequences and the length of the sequence match. The product score is a normalized value between 0 and 100, and is calculated as follows: the BLAST score is multiplied by the percent nucleotide identity and the product is divided by (5 times the length of the shorter of the two sequences). The BLAST score is calculated by assigning a score of +5 for every base that matches in a high-scoring segment pair (HSP), and −4 for every mismatch. Two sequences may share more than one HSP (separated by gaps). If there is more than one HSP, then the pair with the highest BLAST score is used to calculate the product score. The product score represents a balance between fractional overlap and quality in a BLAST alignment. For example, a product score of 100 is produced only for 100% identity over the entire length of the shorter of the two sequences being compared. A product score of 70 is produced either by 100% identity and 70% overlap at one end, or by 88% identity and 100% overlap at the other. A product score of 50 is produced either by 100% identity and 50% overlap at one end, or 79% identity and 100% overlap.

[0326] Alternatively, polynucleotides encoding SECP are analyzed with respect to the tissue sources from which they were derived. For example, some full length sequences are assembled, at least in part, with overlapping Incyte cDNA sequences (see Example III). Each cDNA sequence is derived from a cDNA library constructed from a human tissue. Each human tissue is classified into one of the following organ/tissue categories: cardiovascular system; connective tissue; digestive system; embryonic structures; endocrine system; exocrine glands; genitalia, female; genitalia, male; germ cells; hemic and immune system; liver; musculoskeletal system; nervous system; pancreas; respiratory system; sense organs; skin; stomatognathic system; unclassified/mixed; or urinary tract. The number of libraries in each category is counted and divided by the total number of libraries across all categories. Similarly, each human tissue is classified into one of the following disease/condition categories: cancer, cell line, developmental, inflammation, neurological, trauma, cardiovascular, pooled, and other, and the number of libraries in each category is counted and divided by the total number of libraries across all categories. The resulting percentages reflect the tissue- and disease-specific expression of cDNA encoding SECP. cDNA sequences and cDNA library/tissue information are found in the LIFESEQ GOLD database (Incyte Genomics, Palo Alto Calif.).

[0327] VIII. Extension of SECP Encoding Polynucleotides

[0328] Full length polynucleotides are produced by extension of an appropriate fragment of the full length molecule using oligonucleotide primers designed from this fragment. One primer was synthesized to initiate 5′ extension of the known fragment, and the other primer was synthesized to initiate 3′ extension of the known fragment. The initial primers were designed using OLIGO 4.06 software (National Biosciences), or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the target sequence at temperatures of about 68° C. to about 72° C. Any stretch of nucleotides which would result in hairpin structures and primer-primer dimerizations was avoided.

[0329] Selected human cDNA libraries were used to extend the sequence. If more than one extension was necessary or desired, additional or nested sets of primers were designed.

[0330] High fidelity amplification was obtained by PCR using methods well known in the art. PCR was performed in 96-well plates using the PTC-200 thermal cycler (MJ Research, Inc.). The reaction mix contained DNA template, 200 nmol of each primer, reaction buffer containing Mg²⁺, (NH₄)₂SO₄, and 2-mercaptoethanol, Taq DNA polymerase (Amersham Biosciences), ELONGASE enzyme (Invitrogen), and Pfu DNA polymerase (Stratagene), with the following parameters for primer pair PCI A and PCI B: Step 1: 94° C., 3 min; Step 2: 94° C., 15 sec; Step 3: 60° C., 1 min; Step 4: 68° C., 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68° C., 5 min; Step 7: storage at 4° C. In the alternative, the parameters for primer pair T7 and SK+ were as follows: Step 1: 94° C., 3 min; Step 2: 94° C., 15 sec; Step 3: 57° C., 1 min; Step 4: 68° C., 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68° C., 5 min; Step 7: storage at 4° C.

[0331] The concentration of DNA in each well was determined by dispensing 100 μl PICOGREEN quantitation reagent (0.25% (v/v) PICOGREEN; Molecular Probes, Eugene Oreg.) dissolved in 1×TE and 0.5 μl of undiluted PCR product into each well of an opaque fluorimeter plate (Corning Costar, Acton Mass.), allowing the DNA to bind to the reagent. The plate was scanned in a Fluoroskan II (Labsystems Oy, Helsinki, Finland) to measure the fluorescence of the sample and to quantify the concentration of DNA. A 5 μl to 10 μl aliquot of the reaction mixture was analyzed by electrophoresis on a 1% agarose gel to determine which reactions were successful in extending the sequence.

[0332] The extended nucleotides were desalted and concentrated, transferred to 384-well plates, digested with CviJI cholera virus endonuclease (Molecular Biology Research, Madison Wis.), and sonicated or sheared prior to religation into pUC 18 vector (Amersham Biosciences). For shotgun sequencing, the digested nucleotides were separated on low concentration (0.6 to 0.8%) agarose gels, fragments were excised, and agar digested with Agar ACE (Promega). Extended clones were religated using T4 ligase (New England Biolabs, Beverly Mass.) into pUC 18 vector (Amersham Biosciences), treated with Pfu DNA polymerase (Stratagene) to fill-in restriction site overhangs, and transfected into competent E. coli cells. Transformed cells were selected on antibiotic-containing media, and individual colonies were picked and cultured overnight at 37° C. in 384-well plates in LB/2× carb liquid media.

[0333] The cells were lysed, and DNA was amplified by PCR using Taq DNA polymerase (Amersham Biosciences) and Pfu DNA polymerase (Stratagene) with the following parameters: Step 1: 94° C., 3 min; Step 2: 94° C., 15 sec; Step 3: 60° C., 1 min; Step 4: 72° C., 2 min; Step 5: steps 2, 3, and 4 repeated 29 times; Step 6: 72° C., 5 min; Step 7: storage at 4° C. DNA was quantified by PICOGREEN reagent (Molecular Probes) as described above. Samples with low DNA recoveries were reamplified using the same conditions as described above. Samples were diluted with 20% dimethysulfoxide (1:2, v/v), and sequenced using DYENAMIC energy transfer sequencing primers and the DYENAMIC DIRECT kit (Amersham Biosciences) or the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems).

[0334] In like manner, full length polynucleotides are verified using the above procedure or are used to obtain 5′ regulatory sequences using the above procedure along with oligonucleotides designed for such extension, and an appropriate genomic library.

[0335] IX. Identification of Single Nucleotide Polymorphisms in SECP Encoding Polynucleotides

[0336] Common DNA sequence variants known as single nucleotide polymorphisms (SNPs) were identified in SEQ ID NO:32-62 using the LIFBSEQ database (Incyte Genomics). Sequences from the same gene were clustered together and assembled as described in Example III, allowing the identification of all sequence variants in the gene. An algorithm consisting of a series of filters was used to distinguish SNPs from other sequence variants. Preliminary filters removed the majority of basecall errors by requiring a minimum Phred quality score of 15, and removed sequence alignment errors and errors resulting from improper trimming of vector sequences, chimeras, and splice variants. An automated procedure of advanced chromosome analysis analysed the original chromatogram files in the vicinity of the putative SNP. Clone error filters used statistically generated algorithms to identify errors introduced during laboratory processing, such as those caused by reverse transcriptase, polymerase, or somatic mutation. Clustering error filters used statistically generated algorithms to identify errors resulting from clustering of close homologs or pseudogenes, or due to contamination by non-human sequences. A final set of filters removed duplicates and SNPs found in immunoglobulins or T-cell receptors.

[0337] Certain SNPs were selected for further characterization by mass spectrometry using the high throughput MASSARRAY system (Sequenom, Inc.) to analyze allele frequencies at the SNP sites in four different human populations. The Caucasian population comprised 92 individuals (46 male, 46 female), including 83 from Utah, four French, three Venezualan, and two Amish individuals. The African population comprised 194 individuals (97 male, 97 female), all African Americans. The Hispanic population comprised 324 individuals (162 male, 162 female), all Mexican Hispanic. The Asian population comprised 126 individuals (64 male, 62 female) with a reported parental breakdown of 43% Chinese, 31% Japanese, 13% Korean, 5% Vietnamese, and 8% other Asian. Allele frequencies were first analyzed in the Caucasian population; in some cases those SNPs which showed no allelic variance in this population were not further tested in the other three populations.

[0338] X. Labeling and Use of Individual Hybridization Probes

[0339] Hybridization probes derived from SEQ ID NO:32-62 are employed to screen cDNAs, genomic DNAs, or mRNAs. Although the labeling of oligonucleotides, consisting of about 20 base pairs, is specifically described, essentially the same procedure is used with larger nucleotide fragments. Oligonucleotides are designed using state-of-the-art software such as OLIGO 4.06 software (National Biosciences) and labeled by combining 50 pmol of each oligomer, 250 μCi of [γ-³²P] adenosine triphosphate (Amersham Biosciences), and T4 polynucleotide kinase (DuPont NEN, Boston Mass.). The labeled oligonucleotides are substantially purified using a SEPHADEX G-25 superfine size exclusion dextran bead column (Amersham Biosciences). An aliquot containing 10⁷ counts per minute of the labeled probe is used in a typical membrane-based hybridization analysis of human genomic DNA digested with one of the following endonucleases: Ase I, Bgl II, Eco RI, Pst I, Xba I, or Pvu II (DuPont NEN).

[0340] The DNA from each digest is fractionated on a 0.7% agarose gel and transferred to nylon membranes (Nytran Plus, Schleicher & Schuell, Durham N.H.). Hybridization is carried out for 16 hours at 40° C. To remove nonspecific signals, blots are sequentially washed at room temperature under conditions of up to, for example, 0.1× saline sodium citrate and 0.5% sodium dodecyl sulfate. Hybridization patterns are visualized using autoradiography or an alternative imaging means and compared.

[0341] XI. Microarrays

[0342] The linkage or synthesis of array elements upon a microarray can be achieved utilizing photolithography, piezoelectric printing (ink-jet printing; see, e.g., Baldeschweiler et al., supra), mechanical microspotting technologies, and derivatives thereof. The substrate in each of the aforementioned technologies should be uniform and solid with a non-porous surface (Schena, M., ed. (1999) DNA Microarrays: A Practical Approach, Oxford University Press, London). Suggested substrates include silicon, silica, glass slides, glass chips, and silicon wafers. Alternatively, a procedure analogous to a dot or slot blot may also be used to arrange and link elements to the surface of a substrate using thermal, UV, chemical, or mechanical bonding procedures. A typical array may be produced using available methods and machines well known to those of ordinary skill in the art and may contain any appropriate number of elements (Schena, M. et al. (1995) Science 270:467-470; Shalon, D. et al. (1996) Genome Res. 6:639-645; Marshall, A. and J. Hodgson (1998) Nat. Biotechnol. 16:27-31).

[0343] Full length cDNAs, Expressed Sequence Tags (ESTs), or fragments or oligomers thereof may comprise the elements of the microarray. Fragments or oligomers suitable for hybridization can be selected using software well known in the art such as LASERGENE software (DNASTAR). The array elements are hybridized with polynucleotides in a biological sample. The polynucleotides in the biological sample are conjugated to a fluorescent label or other molecular tag for ease of detection. After hybridization, nonhybridized nucleotides from the biological sample are removed, and a fluorescence scanner is used to detect hybridization at each array element. Alternatively, laser desorbtion and mass spectrometry may be used for detection of hybridization. The degree of complementarity and the relative abundance of each polynucleotide which hybridizes to an element on the microarray may be assessed. In one embodiment, microarray preparation and usage is described in detail below.

[0344] Tissue or Cell Sample Preparation

[0345] Total RNA is isolated from tissue samples using the guanidinium thiocyanate method and poly(A)⁺ RNA is purified using the oligo-(dT) cellulose method. Each poly(A)⁺ RNA sample is reverse transcribed using MMLV reverse-transcriptase, 0.05 pg/μl oligo-(dT) primer (21 mer), 1× first strand buffer, 0.03 units/μl RNase inhibitor, 500 μM dATP, 500 μM dGTP, 500 μM dTTP, 40 μM dCTP, 40 μM dCTP-Cy3 (BDS) or dCTP-Cy5 (Amersham Biosciences). The reverse transcription reaction is performed in a 25 ml volume containing 200 ng poly(A)⁺ RNA with GEMBRIGHT kits (Incyte). Specific control poly(A)⁺ RNAs are synthesized by in vitro transcription from non-coding yeast genomic DNA. After incubation at 37° C. for 2 hr, each reaction sample (one with Cy3 and another with Cy5 labeling) is treated with 2.5 ml of 0.5M sodium hydroxide and incubated for 20 minutes at 85° C. to the stop the reaction and degrade the RNA. Samples are purified using two successive CHROMA SPIN 30 gel filtration spin columns (CLONTECH Laboratories, Inc. (CLONTECH), Palo Alto Calif.) and after combining, both reaction samples are ethanol precipitated using 1 ml of glycogen (1 mg/ml), 60 ml sodium acetate, and 300 ml of 100% ethanol. The sample is then dried to completion using a SpeedVAC (Savant Instruments Inc., Holbrook N.Y.) and resuspended in 14 μl 5×SSC/0.2% SDS.

[0346] Microarray Preparation

[0347] Sequences of the present invention are used to generate array elements. Each array element is amplified from bacterial cells containing vectors with cloned cDNA inserts. PCR amplification uses primers complementary to the vector sequences flanking the cDNA insert. Array elements are amplified in thirty cycles of PCR from an initial quantity of 1-2 ng to a final quantity greater than 5 μg. Amplified array elements are then purified using SEPHACRYL-400 (Amersham Biosciences).

[0348] Purified array elements are immobilized on polymer-coated glass slides. Glass microscope slides (Corning) are cleaned by ultrasound in 0.1% SDS and acetone, with extensive distilled water washes between and after treatments. Glass slides are etched in 4% hydrofluoric acid (VWR Scientific Products Corporation (VWR), West Chester Pa.), washed extensively in distilled water, and coated with 0.05% aminopropyl silane (Sigma) in 95% ethanol. Coated slides are cured in a 110° C. oven.

[0349] Array elements are applied to the coated glass substrate using a procedure described in U.S. Pat. No. 5,807,522, incorporated herein by reference. 1 μl of the array element DNA, at an average concentration of 100 ng/μl, is loaded into the open capillary printing element by a high-speed robotic apparatus. The apparatus then deposits about 5 nl of array element sample per slide.

[0350] Microarrays are UV-crosslinked using a STRATALINKER UV-crosslinker (Stratagene). Microarrays are washed at room temperature once in 0.2% SDS and three times in distilled water. Non-specific binding sites are blocked by incubation of microarrays in 0.2% casein in phosphate buffered saline (PBS) (Tropix, Inc., Bedford Mass.) for 30 minutes at 60° C. followed by washes in 0.2% SDS and distilled water as before.

[0351] Hybridization

[0352] Hybridization reactions contain 9 μl of sample mixture consisting of 0.2 μg each of Cy3 and Cy5 labeled cDNA synthesis products in 5×SSC, 0.2% SDS hybridization buffer. The sample mixture is heated to 65° C. for 5 minutes and is aliquoted onto the microarray surface and covered with an 1.8 cm² coverslip. The arrays are transferred to a waterproof chamber having a cavity just slightly larger than a microscope slide. The chamber is kept at 100% humidity internally by the addition of 140 μl of 5×SSC in a corner of the chamber. The chamber containing the arrays is incubated for about 6.5 hours at 60° C. The arrays are washed for 10 min at 45° C. in a first wash buffer (1×SSC, 0.1% SDS), three times for 10 minutes each at 45° C. in a second wash buffer (0.1×SSC), and dried.

[0353] Detection

[0354] Reporter-labeled hybridization complexes are detected with a microscope equipped with an Innova 70 mixed gas 10 W laser (Coherent, Inc., Santa Clara Calif.) capable of generating spectral lines at 488 nm for excitation of Cy3 and at 632 nm for excitation of Cy5. The excitation laser light is focused on the array using a 20× microscope objective (Nikon, Inc., Melville N.Y.). The slide containing the array is placed on a computer-controlled X-Y stage on the microscope and raster-scanned past the objective. The 1.8 cm×1.8 cm array used in the present example is scanned with a resolution of 20 micrometers.

[0355] In two separate scans, a mixed gas multiline laser excites the two fluorophores sequentially. Emitted light is split, based on wavelength, into two photomultiplier tube detectors (PMT R1477, Hamamatsu Photonics Systems, Bridgewater N.J.) corresponding to the two fluorophores. Appropriate filters positioned between the array and the photomultiplier tubes are used to filter the signals. The emission maxima of the fluorophores used are 565 nm for Cy3 and 650 nm for Cy5. Each array is typically scanned twice, one scan per fluorophore using the appropriate filters at the laser source, although the apparatus is capable of recording the spectra from both fluorophores simultaneously.

[0356] The sensitivity of the scans is typically calibrated using the signal intensity generated by a cDNA control species added to the sample mixture at a known concentration. A specific location on the array contains a complementary DNA sequence, allowing the intensity of the signal at that location to be correlated with a weight ratio of hybridizing species of 1:100,000. When two samples from different sources (e.g., representing test and control cells), each labeled with a different fluorophore, are hybridized to a single array for the purpose of identifying genes that are differentially expressed, the calibration is done by labeling samples of the calibrating cDNA with the two fluorophores and adding identical amounts of each to the hybridization mixture.

[0357] The output of the photomultiplier tube is digitized using a 12-bit RTI-835H analog-to-digital (A/D) conversion board (Analog Devices, Inc., Norwood Mass.) installed in an IBM-compatible PC computer. The digitized data are displayed as an image where the signal intensity is mapped using a linear 20-color transformation to a pseudocolor scale ranging from blue (low signal) to red (high signal). The data is also analyzed quantitatively. Where two different fluorophores are excited and measured simnultaneously, the data are first corrected for optical crosstalk (due to overlapping emission spectra) between the fluorophores using each fluorophore's emission spectrum.

[0358] A grid is superimposed over the fluorescence signal image such that the signal from each spot is centered in each element of the grid. The fluorescence signal within each element is then integrated to obtain a numerical value corresponding to the average intensity of the signal. The software used for signal analysis is the GEMTOOLS gene expression analysis program (Incyte). Array elements that exhibited at least about a two-fold change in expression, a signal-to-background ratio of at least 2.5, and an element spot size of at least 40% were identified as differentially expressed using the GEMTOOLS program (Incyte Genomics).

[0359] Expression

[0360] SEQ ID NO:36 showed differential expression in association with colon cancer, as determined by microarray analysis. Gene expression profiles were obtained by comparing the results of competitive hybridization experiments between normal colon tissue and tumorous colon tissue samples from the same donor (Huntsman Cancer Institute, Salt Lake City, Utah). In separate matched tissue experiments, the expression of SEQ ID NO:36 was decreased by at least two-fold in the tumorous colon tissue as compared to grossly uninvolved colon tissue originating from the matched donors. Therefore, in various embodiments, SEQ ID NO:36 can be used for one or more of the following: i) monitoring treatment of colon cancer, ii) diagnostic assays for colon cancer, and iii) developing therapeutics and/or other treatments for colon cancer.

[0361] XII. Complementary Polynucleotides

[0362] Sequences complementary to the SECP-encoding sequences, or any parts thereof, are used to detect, decrease, or inhibit expression of naturally occurring SECP. Although use of oligonucleotides comprising from about 15 to 30 base pairs is described, essentially the same procedure is used with smaller or with larger sequence fragments. Appropriate oligonucleotides are designed using OLIGO 4.06 software (National Biosciences) and the coding sequence of SECP. To inhibit transcription, a complementary oligonucleotide is designed from the most unique 5′ sequence and used to prevent promoter binding to the coding sequence. To inhibit translation, a complementary oligonucleotide is designed to prevent ribosomal binding to the SECP-encoding transcript.

[0363] XIII. Expression of SECP

[0364] Expression and purification of SECP is achieved using bacterial or virus-based expression systems. For expression of SECP in bacteria, cDNA is subcloned into an appropriate vector containing an antibiotic resistance gene and an inducible promoter that directs high levels of cDNA transcription. Examples of such promoters include, but are not limited to, the trp-lac (tac) hybrid promoter and the T5 or T7 bacteriophage promoter in conjunction with the lac operator regulatory element. Recombinant vectors are transformed into suitable bacterial hosts, e.g., BL21(DE3). Antibiotic resistant bacteria express SECP upon induction with isopropyl beta-D-thiogalactopyranoside (IPTG). Expression of SECP in eukaryotic cells is achieved by infecting insect or mammalian cell lines with recombinant Autographica californica nuclear polyhedrosis virus (AcMNPV), commonly known as baculovirus. The nonessential polyhedrin gene of baculovirus is replaced with cDNA encoding SECP by either homologous recombination or bacterial-mediated transposition involving transfer plasmid intermediates. Viral infectivity is maintained and the strong polyhedrin promoter drives high levels of cDNA transcription. Recombinant baculovirus is used to infect Spodoptera frugiperda (Sf9) insect cells in most cases, or human hepatocytes, in some cases. Infection of the latter requires additional genetic modifications to baculovirus (Engelhard, E. K. et al. (1994) Proc. Natl. Acad. Sci. USA 91:3224-3227; Sandig, V. et al. (1996) Hum. Gene Ther. 7:1937-1945).

[0365] In most expression systems, SECP is synthesized as a fusion protein with, e.g., glutathione S-transferase (GST) or a peptide epitope tag, such as FLAG or 6-His, permitting rapid, single-step, affinity-based purification of recombinant fusion protein from crude cell lysates. GST, a 26-kilodalton enzyme from Schistosoma japonicum, enables the purification of fusion proteins on immobilized glutathione under conditions that maintain protein activity and antigenicity (Amersham Biosciences). Following purification, the GST moiety can be proteolytically cleaved from SECP at specifically engineered sites. FLAG, an 8-amino acid peptide, enables immunoaffinity purification using commercially available monoclonal and polyclonal anti-FLAG antibodies (Eastman Kodak). 6-His, a stretch of six consecutive histidine residues, enables purification on metal-chelate resins (QIAGEN). Methods for protein expression and purification are discussed in Ausubel et al. (supra, ch. 10 and 16). Purified SECP obtained by these methods can be used directly in the assays shown in Examples XVII, XVIII, XIX, and XX where applicable.

[0366] XIV. Functional Assays

[0367] SECP function is assessed by expressing the sequences encoding SECP at physiologically elevated levels in mammalian cell culture systems. cDNA is subcloned into a mammalian expression vector containing a strong promoter that drives high levels of cDNA expression. Vectors of choice include PCMV SPORT plasmid (Invitrogen, Carlsbad Calif.) and PCR3.1 plasmid (Invitrogen), both of which contain the cytomegalovirus promoter. 5-10 μg of recombinant vector are transiently transfected into a human cell line, for example, an endothelial or hematopoietic cell line, using either liposome formulations or electroporation. 1-2 μg of an additional plasmid containing sequences encoding a marker protein are co-transfected. Expression of a marker protein provides a means to distinguish transfected cells from nontransfected cells and is a reliable predictor of cDNA expression from the recombinant vector. Marker proteins of choice include, e.g., Green Fluorescent Protein (GFP; Clontech), CD64, or a CD64-GFP fusion protein. Flow cytometry (FCM), an automated, laser optics-based technique, is used to identify transfected cells expressing GFP or CD64-GFP and to evaluate the apoptotic state of the cells and other cellular properties. FCM detects and quantifies the uptake of fluorescent molecules that diagnose events preceding or coincident with cell death. These events include changes in nuclear DNA content as measured by staining of DNA with propidium iodide; changes in cell size and granularity as measured by forward light scatter and 90 degree side light scatter; down-regulation of DNA synthesis as measured by decrease in bromodeoxyuridine uptake; alterations in expression of cell surface and intracellular proteins as measured by reactivity with specific antibodies; and alterations in plasma membrane composition as measured by the binding of fluorescein-conjugated Annexin V protein to the cell surface. Methods in flow cytometry are discussed in Ormerod, M. G. (1994; Flow Cytometry, Oxford, New York N.Y.).

[0368] The influence of SECP on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding SECP and either CD64 or CD64-GFP. CD64 and CD64-GFP are expressed on the surface of transfected cells and bind to conserved regions of human immunoglobulin G (IgG). Transfected cells are efficiently separated from nontransfected cells using magnetic beads coated with either human IgG or antibody against CD64 (DYNAL, Lake Success N.Y.). mRNA can be purified from the cells using methods well known by those of skill in the art. Expression of mRNA encoding SECP and other genes of interest can be analyzed by northern analysis or microarray techniques.

[0369] XV. Production of SECP Specific Antibodies

[0370] SECP substantially purified using polyacrylamide gel electrophoresis (PAGE; see, e.g., Harrington, M. G. (1990) Methods Enzymol. 182:488-495), or other purification techniques, is used to immunize animals (e.g., rabbits, mice, etc.) and to produce antibodies using standard protocols.

[0371] Alternatively, the SECP amino acid sequence is analyzed using LASERGENE software (DNASTAR) to determine regions of high immunogenicity, and a corresponding oligopeptide is synthesized and used to raise antibodies by means known to those of skill in the art. Methods for selection of appropriate epitopes, such as those near the C-terminus or in hydrophilic regions are well described in the art (Ausubel et al., supra, ch. 11).

[0372] Typically, oligopeptides of about 15 residues in length are synthesized using an ABI 431A peptide synthesizer (Applied Biosystems) using FMOC chemistry and coupled to KLH (Sigma-Aldrich, St. Louis Mo.) by reaction with N-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) to increase immunogenicity (Ausubel et al., supra). Rabbits are immunized with the oligopeptide-KLH complex in complete Freund's adjuvant. Resulting antisera are tested for antipeptide and anti-SECP activity by, for example, binding the peptide or SECP to a substrate, blocking with 1% BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated goat anti-rabbit IgG.

[0373] XVI. Purification of Naturally Occurring SECP Using Specific Antibodies

[0374] Naturally occurring or recombinant SECP is substantially purified by immunoaffinity chromatography using antibodies specific for SECP. An immunoaffinity column is constructed by covalently coupling anti-SECP antibody to an activated chromatographic resin, such as CNBr-activated SEPHAROSE (Amersham Biosciences). After the coupling, the resin is blocked and washed according to the manufacturer's instructions.

[0375] Media containing SECP are passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of SECP (e.g., high ionic strength buffers in the presence of detergent). The column is eluted under conditions that disrupt antibody/SECP binding (e.g., a buffer of pH 2 to pH 3, or a high concentration of a chaotrope, such as urea or thiocyanate ion), and SECP is collected.

[0376] XVII. Identification of Molecules Which Interact with SECP

[0377] SECP, or biologically active fragments thereof, are labeled with ¹²⁵I Bolton-Hunter reagent (Bolton, A. E. and W. M. Hunter (1973) Biochem. J. 133:529-539). Candidate molecules previously arrayed in the wells of a multi-well plate are incubated with the labeled SECP, washed, and any wells with labeled SECP complex are assayed. Data obtained using different concentrations of SECP are used to calculate values for the number, affinity, and association of SECP with the candidate molecules.

[0378] Alternatively, molecules interacting with SECP are analyzed using the yeast two-hybrid system as described in Fields, S. and O. Song (1989; Nature 340:245-246), or using commercially available kits based on the two-hybrid system, such as the MATCHMAKER system (Clontech).

[0379] SECP may also be used in the PATHCALLING process (CuraGen Corp., New Haven Conn.) which employs the yeast two-hybrid system in a high-throughput manner to determine all interactions between the proteins encoded by two large libraries of genes (Nandabalan, K. et al. (2000) U.S. Pat. No. 6,057,101).

[0380] XVIII. Demonstration of SECP Activity

[0381] An assay for growth stimulating or inhibiting activity of SECP measures the amount of DNA synthesis in Swiss mouse 3T3 cells (McKay, I. and I. Leigh, eds. (1993) Growth Factors: A Practical Approach, Oxford University Press, New York, N.Y.). In this assay, varying amounts of SECP are added to quiescent 3T3 cultured cells in the presence of [³H]thymidine, a radioactive DNA precursor. SECP for this assay can be obtained by recombinant means or from biochemical preparations. Incorporation of [³H]thymidine into acid-precipitable DNA is measured over an appropriate time interval, and the amount incorporated is directly proportional to the amount of newly synthesized DNA. A linear dose-response curve over at least a hundred-fold SECP concentration range is indicative of growth modulating activity. One unit of activity per milliliter is defined as the concentration of SECP producing a 50% response level, where 100% represents maximal incorporation of [³}]thymidine into acid-precipitable DNA.

[0382] Alternatively, an assay for SECP activity measures the stimulation or inhibition of neurotransmission in cultured cells. Cultured CHO fibroblasts are exposed to SECP. Following endocytic uptake of SECP, the cells are washed with fresh culture medium, and a whole cell voltage-clamped Xenopus myocyte is manipulated into contact with one of the fibroblasts in SECP-free medium. Membrane currents are recorded from the myocyte. Increased or decreased current relative to control values are indicative of neuromodulatory effects of SECP (Morimoto, T. et al. (1995) Neuron 15:689-696).

[0383] Alternatively, an assay for SECP activity measures the amount of SECP in secretory, membrane-bound organelles. Transfected cells as described above are harvested and lysed. The lysate is fractionated using methods known to those of skill in the art, for example, sucrose gradient ultracentrifugation. Such methods allow the isolation of subcellular components such as the Golgi apparatus, ER, small membrane-bound vesicles, and other secretory organelles. Immunoprecipitations from fractionated and total cell lysates are performed using SECP-specific antibodies, and immunoprecipitated samples are analyzed using SDS-PAGE and immunoblotting techniques. The concentration of SECP in secretory organelles relative to SECP in total cell lysate is proportional to the amount of SECP in transit through the secretory pathway.

[0384] Alternatively, AMP binding activity is measured by combining SECP with ³²P-labeled AMP. The reaction is incubated at 37° C. and terminated by addition of trichloroacetic acid. The acid extract is neutralized and subjected to gel electrophoresis to remove unbound label. The radioactivity retained in the gel is proportional to SECP activity.

[0385] XIX. SECP Secretion Assay

[0386] A high throughput assay may be used to identify polypeptides that are secreted in eukaryotic cells. In an example of such an assay, polypeptide expression libraries are constructed by fusing 5′-biased cDNAs to the 5′-end of a leaderless β-lactamase gene. β-lactamase is a convenient genetic reporter as it provides a high signal-to-noise ratio against low endogenous background activity and retains activity upon fusion to other proteins. A dual promoter system allows the expression of β-lactamase fusion polypeptides in bacteria or eukaryotic cells, using the lac or CMV promoter, respectively.

[0387] Libraries are first transformed into bacteria, e.g., E. coli, to identify library members that encode fusion polypeptides capable of being secreted in a prokaryotic system. Mammalian signal sequences direct the translocation of β-lactamase fusion polypeptides into the periplasm of bacteria where it confers antibiotic resistance to carbenicillin. Carbenicillin-selected bacteria are isolated on solid media, individual clones are grown in liquid media, and the resulting cultures are used to isolate library member plasmid DNA.

[0388] Mammalian cells, e.g., 293 cells, are seeded into 96-well tissue culture plates at a density of about 40,000 cells/well in 100 μl phenol red-free DME supplemented with 10% fetal bovine serum (FBS) (Life Technologies, Rockville, Md.). The following day, purified plasmid DNAs isolated from carcenicillin-resistant bacteria are diluted with 15 μl OPTI-MEM I medium (Life Technologies) to a volume of 25 μl for each well of cells to be transfected. In separate plates, 1 μl LF2000 Reagent (Life Technologies) is diluted into 25 μl/well OPTI-MEM I. The 25 μl diluted LF2000 Reagent is then combined with the 25 μl diluted DNA, mixed briefly, and incubated for 20 minutes at room temperature. The resulting DNA-LF2000 reagent complexes are then added directly to each well of 293 cells. Cells are also transfected with appropriate control plasmids expressing either wild-type β-lactamase, leaderless β-lactamase, or, for example, CD4-fused leaderless β-lactamase. 24 hrs following transfection, about 90 μl of cell culture media are assayed at 37° C. with 100 mM Nitrocefin (Calbiochem, San Diego, Calif.) and 0.5 mM oleic acid (Sigma Corp. St. Louis, Mo.) in 10 mM phosphate buffer (pH 7.0). Nitrocefin is a substrate for β-lactamase that undergoes a noticeable color change from yellow to red upon hydrolysis. β-lactamase activity is monitored over 20 min in a microtiter plate reader at 486 nm. Increased color absorption at 486 nm corresponds to secretion of a β-lactamase fusion polypeptide in the transfected cell media, resulting from the presence of a eukaryortic signal sequence in the fusion polypeptide. Polynucleotide sequence analysis of the corresponding library member plasmid DNA is then used to identify the signal sequence-encoding cDNA.

[0389] For example, SEQ ID NO:4 and SEQ ID NO:14 were found to be secreted polypeptides using this assay.

[0390] XX. Demonstration of Immunoglobulin Activity

[0391] An assay for SECP activity measures the ability of SECP to recognize and precipitate antigens from serum. This activity can be measured by the quantitative precipitin reaction. (Golub, E. S. et al. (1987) Immunology: A Synthesis, Sinauer Associates, Sunderland, MA, pp. 113-115.) SECP is isotopically labeled using methods known in the art. Various serum concentrations are added to constant amounts of labeled SECP. SECP-antigen complexes precipitate out of solution and are collected by centrifugation. The amount of precipitable SECP-antigen complex is proportional to the amount of radioisotope detected in the precipitate. The amount of precipitable SECP-antigen complex is plotted against the serum concentration. For various serum concentrations, a characteristic precipitin curve is obtained, in which the amount of precipitable SECP-antigen complex initially increases proportionately with increasing serum concentration, peaks at the equivalence point, and then decreases proportionately with further increases in serum concentration. Thus, the amount of precipitable SECP-antigen complex is a measure of SECP activity which is characterized by sensitivity to both limiting and excess quantities of antigen.

[0392] Alternatively, an assay for SECP activity measures the expression of SECP on the cell surface. cDNA encoding SECP is transfected into a non-leukocytic cell line. Cell surface proteins are labeled with biotin (de la Fuente, M. A. et al. (1997) Blood 90:2398-2405). Immunoprecipitations are performed using SECP-specific antibodies, and immunoprecipitated samples are analyzed using SDS-PAGE and immunoblotting techniques. The ratio of labeled immunoprecipitant to unlabeled immunoprecipitant is proportional to the amount of SECP expressed on the cell surface.

[0393] Alternatively, an assay for SECP activity measures the amount of cell aggregation induced by overexpression of SECP. In this assay, cultured cells such as NIH3T3 are transfected with cDNA encoding SECP contained within a suitable mammalian expression vector under control of a strong promoter. Cotransfection with cDNA encoding a fluorescent marker protein, such as Green Fluorescent Protein (CLONTECH), is useful for identifying stable transfectants. The amount of cell agglutination, or clumping, associated with transfected cells is compared with that associated with untransfected cells. The amount of cell agglutination is a direct measure of SECP activity.

[0394] Various modifications and variations of the described compositions, methods, and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. It will be appreciated that the invention provides novel and useful proteins, and their encoding polynucleotides, which can be used in the drug discovery process, as well as methods for using these compositions for the detection, diagnosis, and treatment of diseases and conditions. Although the invention has been described in connection with certain embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Nor should the description of such embodiments be considered exhaustive or limit the invention to the precise forms disclosed. Furthermore, elements from one embodiment can be readily recombined with elements from one or more other embodiments. Such combinations can form a number of embodiments within the scope of the invention. It is intended that the scope of the invention be defined by the following claims and their equivalents. TABLE 1 Poly- Poly- Incyte Incyte peptide Incyte nucleotide Poly- Project SEQ Polypeptide SEQ nucleotide ID ID NO: ID ID NO: ID Incyte Full Length Clones 7475736 1 7475736CD1 32 7475736CB1 5742041CA2 859872 2 859872CD1 33 859872CB1 1893683 3 1893683CD1 34 1893683CB1 2824347 4 2824347CD1 35 2824347CB1 90132180CA2 5055878 5 5055878CD1 36 5055878CB1 6073505CA2, 6075616CA2 7473596 6 7473596CD1 37 7473596CB1 56006939CA2, 56007163CA2, 90132157CA2, 90132165CA2, 90132189CA2, 90132225CA2, 90132289CA2, 90132290CA2, 90132309CA2, 90132325CA2, 90132334CA2, 90132390CA2, 90132401CA2, 90132433CA2, 90132441CA2, 90132458CA2, 90132474CA2 7497718 7 7497718CD1 38 7497718CB1 7341722CA2 7498077 8 7498077CD1 39 7498077CB1 1633319 9 1633319CD1 40 1633319CB1 1712631 10 1712631CD1 41 1712631CB1 6781380CA2, 90203175CA2, 90203183CA2, 90203283CA2, 95035514CA2, 95035662CA2, 95035670CA2 1795426 11 1795426CD1 42 1795426CB1 1329584 12 1329584CD1 43 1329584CB1 1329584CA2, 3045256CA2, 5596442CA2, 6885664CA2, 90144601CA2, 90144725CA2, 90144974CA2 3592659 13 3592659CD1 44 3592659CB1 7596081 14 7596081CD1 45 7596081CB1 3009869 15 3009869CD1 46 3009869CB1 7349094 16 7349094CD1 47 7349094CB1 6826956 17 6826956CD1 48 6826956CB1 7486351 18 7486351CD1 49 7486351CB1 1709023 19 1709023CD1 50 1709023CB1 4721928CA2, 90100351CA2, 90100359CA2, 90100367CA2, 90100391CA2, 90100483CA2, 90100491CA2 1556012 20 1556012CD1 51 1556012CB1 1556012CA2 1838010 21 1838010CD1 52 1838010CB1 90199942CA2, 90199950CA2 1741076 22 1741076CD1 53 1741076CB1 1741076CA2, 1742752CA2, 90127504CA2, 90127544CA2, 90127620CA2, 90127639CA2, 90127644CA2, 90127676CA2, 90131080CA2 2692031 23 2692031CD1 54 2692031CB1 90066195CA2, 90066263CA2 7237245 24 7237245CD1 55 7237245CB1 7488021 25 7488021CD1 56 7488021CB1 7390973 26 7390973CD1 57 7390973CB1 90114919CA2, 90115003CA2, 90115043CA2 4890777 27 4890777CD1 58 4890777CB1 4890777CA2, 90109915CA2, 90109923CA2, 90109939CA2, 90109947CA2, 90110007CA2, 90110031CA2, 90110039CA2, 90110047CA2 5511444 28 5511444CD1 59 5511444CB1 5510850CA2, 5511444CA2 6104370 29 6104370CD1 60 6104370CB1 2047130CA2, 6104370CA2 7488468 30 7488468CD1 61 7488468CB1 7503555 31 7503555CD1 62 7503555CB1

[0395] TABLE 2 Incyte GenBank ID NO: Polypeptide Polypeptide or PROTEOME Probability SEQ ID NO: ID ID NO: Score Annotation 3 1893683CD1 g18252514 9.0E−43 [Homo sapiens] hepatocellular carcinoma-associated antigen HCA557b 4 2824347CD1 g11526769 2.0E−31 [Danio rerio] Slit3 Itoh, A., Miyabayashi, T., Ohno, M. and Sakano, S. (1998) Cloning and expressions of three mammalian homologues of Drosophila slit suggest possible roles for Slit in the formation and maintenance of the nervous system Brain Res. Mol. Brain Res. 62 (2), 175-186 5 5055878CD1 g12843712  1.0E−105 [Mus musculus] Immunoglobulin domain containing protein-data source: Pfam, source key: PF00047, evidence: ISS˜putative 10 1712631CD1 g2062022 2.4E−14 [Homo sapiens] putative progesterone binding protein Gerdes, D., Wehling, M., Leube, B. and Falkenstein, E. (1998) Cloning and tissue expression of two putative steroid membrane receptors Biol. Chem. 379 (7), 907-911 13 3592659CD1 g15053987 0.0 [Homo sapiens] c-Mpl binding protein 16 7349094CD1 g915208 2.1E−24 [Sus scrofa] gastric mucin Turner, B. S. et al. (1995) Biochem. J. 308: 89-96 Turner, B. S. et al. (1999) Biochim. Biophys. Acta 1447(1): 77-92 17 6826956CD1 g2010 4.7E−91 [Sus scrofa] link protein precursor (AA-15 to 339) Perkins, S. J., Nealis, A. S., Dudhia, J. and Hardingham, T. E. (1989) J. Mol. Biol. 206: 737-753 Neame, P. J. and F. P. Barry (1994) EXS 70: 53-72 18 7486351CD1 g13568984  1.3E−228 [Cercopithecus aethiops] growth/differentiation factor 7 growth/differentiation factor 7 Watakabe, A. et al. (2001) J. Neurochem. 76: 1455-1464 19 1709023CD1 g6063092 1.3E−97 [Homo sapiens] F-box protein FBX29 F-box protein FBX29 Winston, J. T. et al. (1999) Curr Biol. 9(20): 1180-2 20 1556012CD1 g14270364 2.7E−49 [Mus musculus] Epigen protein Strachan, L. et al. (2001) J. Biol. Chem. 276: 18265-18271 21 1838010CD1 g3776468 8.3E−12 [Homo sapiens] immunoglobulin-like transcript 10 protein Torkar, M. et al. (1998) Eur. J. Immunol. 28: 3959-3967 Isotypic variation of novel immunoglobulin-like transcript/killer cell inhibitory receptor loci in the leukocyte receptor complex 24 7237245CD1 g19388008  1.0E−160 [Mus musculus] WD repeat domain 5 25 7488021CD1 g5019774 2.2E−54 [Homo sapiens] taxol resistant associated protein (TRAG-3 variant) Duan Z. et al. (1999) Gene 229: 75-81 TRAG-3, a novel gene, isolated from a taxol-resistant ovarian carcinoma cell line 26 7390973CD1 g2062694 1.5E−53 [Homo sapiens] butyrophilin Tazi-Ahnini, R. et al. (1997) Immunogenetics 1997; 47(1): 55-63 Ruddy, D. A. et al. (1997) Genome Res. 1997 May; 7(5): 441-56

[0396] TABLE 3 Amino SEQ Incyte Acid Potential Potential ID Polypeptide Resi- Phosphorylation Glycosylation Analytical Methods NO: ID dues Sites Sites Signature Sequences, Domains and Motifs and Databases 1 7475736CD1 403 S176 S178 S191 N42 N105 N285 signal_cleavage: M1-S27 SPSCAN S237 T115 T151 T241 T295 T309 T338 Signal Peptide: M1-Q29 HMMER Fibronectin type III domain: P243-R326 HMMER_PFAM Gonadotropin-releasing hormone BL00473: BLIMPS_BLOCKS Q298-G307 2 859872CD1 993 S51 S139 S241 N370 N818 N913 signal_cleavage: M1-V22 SPSCAN S346 S347 S355 S357 S361 S444 S448 S489 S542 S569 S716 S823 S845 S890 S927 T58 T150 T252 T326 T382 T400 T766 T806 T850 T852 T857 T979 Y419 PQQ enzyme repeat K52-A89, K534-K571 HMMER_PFAM PROTEIN H17B01.4 C25H1.07 CHROMOSOME I BLAST_PRODOM APA1/DTPPDI1 INTERGENIC REGION PD018547: K544-W992, G269-L302 Leucine zipper pattern: L481-L502 MOTIFS 3 1893683CD1 127 S68 S98 S120 T55 N28 signal_cleavage: M1-S54 SPSCAN T122 4 2824347CD1 590 Signal Peptide: M1-A33 HMMER Signal Peptide: M12-A30 HMMER Signal Peptide: M12-A33 HMMER Signal Peptide: M12-P35 HMMER Signal Peptide: M1-A30 HMMER Signal Peptide: M12-R32 HMMER 5 5055878CD1 262 S91 S93 S126 S160 N58 N83 N118 signal_cleavage: M1-T27 SPSCAN S200 T60 T102 N158 N190 T132 T183 Y68 Signal Peptide: M1-S28 HMMER Signal Peptide: M11-S28 HMMER Signal Peptide: M9-S28 HMMER Immunoglobulin domain: G136-A197, HMMER_PFAM G47-L105 Cytosolic domain: R242-L262 TMHMMER Transmembrane domain: V219-A241 Non-cytosolic domain: M1-G218 6 7473596CD1 122 S74 N64 N93 N96 N99 signal_cleavage: M1-A16 SPSCAN Signal Peptide: M1-A16 HMMER Signal Peptide: M1-D22 HMMER Signal Peptide: M1-S18 HMMER Signal Peptide: M1-P19 HMMER 7 7497718CD1 140 S115 T43 T76 T90 signal_cleavage: M1-M15 SPSCAN Signal Peptide: M1-M15 HMMER Signal Peptide: M15-A44 HMMER 8 7498077CD1 776 S75 S109 S182 N189 N257 N269 Signal Peptide: M1-S20 HMMER S338 S430 S481 N282 N309 N319 S576 S580 S606 N405 N428 N462 S730 T66 T149 T205 T626 Cytosolic domain: K545-T776 TMHMMER Transmembrane domain: A525-L544 Non-cytosolic domain: M1-W524 9 1633319CD1 428 S50 S110 S253 N3 signal_cleavage: M1-S26 SPSCAN S281 S311 S318 S377 S392 S406 S419 T142 T198 T203 T248 T340 Y357 10 1712631CD1 264 S68 S109 S121 signal_cleavage: M1-A22 SPSCAN S181 S190 T134 T149 Signal Peptide: M1-A16 HMMER Signal Peptide: M1-A22 HMMER Cytosolic domain: M1-G6 TMHMMER Transmembrane domain: R7-W29 Non-cytosolic domain: G30-L264 PROTEIN BINDING PUTATIVE BLAST_PRODOM PROGESTERONE CHROMOSOME MEMBRANE STEROID ASSOCIATED RECEPTOR COMPONENT PD006731: P31-R132 11 1795426CD1 437 S72 S117 S249 N120 N383 signal_cleavage: M1-A45 SPSCAN S257 S302 S319 S390 T92 T95 Signal Peptide: L30-A45, L30-C48, HMMER M1-C48, P23-A45, P27-C48, R22-A45, Q19-A45, C26-A45, P27-A45 12 1329584CD1 83 S17 S35 signal_cleavage: M1-S19 SPSCAN Signal Peptide: M1-S19, M1-L21 HMMER 13 3592659CD1 445 S42 S74 S115 S144 N81 N135 N344 signal_cleavage: M1-A58 SPSCAN S195 S244 S356 S394 S404 T78 T83 T167 T168 T210 Y72 Y291 PROTEIN LA RIBONUCLEOPROTEIN - BLAST_PRODOM AUTOANTIGEN RNABINDING NUCLEAR HOMOLOG LUPUS PHOSPHORYLATION B PD004143: E109-S195 14 7596081CD1 563 S37 S38 S134 S137 N35 N109 N250 signal_cleavage: M1-A29 SPSCAN S140 S178 S252 N458 N468 S291 S351 S524 T218 T503 Y147 Signal Peptide: L12-A29, M1-A29, HMMER P7-A29, R10-A29, L9-A29, R5-A29 Cytosolic domain: K210-M221, T282-K293, TMHMMER H354-Q359 Transmembrane domain: T187-L209, F222-A244, L259-V281, L294-F316, Y331-R353, P360-I382 Non-cytosolic domain: M1-E186, T245-K258, D317- 15 3009869CD1 410 S26 S29 S70 S72 N87 N267 signal_cleavage: M1-G14 SPSCAN S89 S93 S97 S112 S211 S321 S356 S372 T181 T196 T274 Y304 16 7349094CD1 1461 S9 S25 S99 S240 N409 N434 N488 Wilm's tumour protein signature PR00049: BLIMPS_PRINTS S247 S248 S266 N567 N595 N934 G4-A20, H1262-P1276 S353 S374 S512 N1015 N1043 S597 S745 S766 N1187 N1392 S812 S816 S826 S860 S877 S892 S917 S925 S932 S991 S1005 S1017 S1021 S1070 S1077 S1094 S1099 S1108 S1136 S1144 S1180 S1188 S1197 S1402 S1416 S1435 T148 T151 T216 T226 T312 T332 T572 T621 T715 T734 T788 T1034 T1050 T1335 T1353 Y133 Y869 MUCIN; MUC5; TRACHEOBRONCHIAL; BLAST_DOMO DM05454|S55316|1-317: E386-S655 17 6826956CD1 402 S58 S111 S327 N132 signal_cleavage: M1-A29 SPSCAN T134 T177 T355 Y262 Signal Peptide: M1-G19 HMMER Signal Peptide: M1-A29 HMMER Extracellular link domain: G162-F267, HMMER_PFAM G273-Y364 Immunoglobulin domain: G61-V145 HMMER_PFAM Cytosolic: M1-A6 TMHMMER Transmembrane: A7-A29 Non-cytosolic: Q30-V402 Link domain proteins BL01241: E180-G232 BLIMPS_BLOCKS GLYCOPROTEIN PRECURSOR PROTEIN BLAST_PRODOM PROTEOGLYCAN SIGNAL REPEAT CORE EGF- LIKE DOMAIN IMMUNOGLOBULIN PF000918: G162-F267, F286-Y364 DM00260 COMPLEMENT FACTOR H REPEAT BLAST_DOMO |P55252|151-254: M155-S269, F286-Y364 |P55252|256-353: N270-A366, K175-C230 |P55252| 256-353: L271-A366, D159-N270 DM00001| IMMUNOGLOBULIN |P55252|43-149: Q55-D152 Link domain signature: C185-C230 MOTIFS 18 7486351CD1 450 S133 S147 S166 N83 signal_cleavage: M1-P19 SPSCAN S260 S271 S279 S309 S350 S388 T129 T274 T322 Signal Peptide: M1-A25 HMMER Signal Peptide: M1-C17 HMMER Signal Peptide: M1-G22 HMMER Signal Peptide: M1-P19 HMMER Transforming growth factor beta like: HMMER_PFAM R346-R450 TGF-beta propeptide: A65-S272 HMMER_PFAM TGF-beta family proteins BL00250: BLIMPS_BLOCKS C349-F384, C414-C449 TGF-beta family signature: S347-N403 PROFILESCAN Inhibin alpha chain signature PR00669: BLIMPS_PRINTS C349-W366, W366-D383 GLYCOPROTEIN PRECURSOR SIGNAL BLAST_PRODOM GROWTH FACTOR PROTEIN CYTOKINE BETA BONE MORPHOGENETIC PD000357: C349-R450 DM00245 TGF-BETA FAMILY BLAST_DOMO |P43026|174-501: R317-R450, M93-A288 |I49541|105-420: H341-R450, R117-Q287 |P12643| 88-396: R343-R450, R117-R219 |P34821|74-399: G340-C449, F91-S166 TGF-beta family signature: I367-C382 MOTIFS 19 1709023CD1 203 S95 S103 S182 N44 Signal Peptide: M1-S23 HMMER T153 signal_cleavage: M53-A85 SPSCAN WD domain, G-beta repeat: I72-D106, HMMER_PFAM R29-D66 Trp-Asp (WD-40) repeats signature: V62-Y139 PROFILESCAN G-protein beta WD-40 repeat signature BLIMPS_PRINTS PR00320: M53-L67, I93-Y107 20 1556012CD1 133 signal_cleavage: M1-A23 SPSCAN Signal Peptide: M1-A23 HMMER EGF-like domain: C51-C86 HMMER_PFAM Non-cytosolic domain: M1-K101 TMHMMER Transmembrane domain: Y102-I124 Cytosolic domain: R125-I133 Flavodoxin signature: V9-S48 PROFILESCAN Type I EGF signature PR00009: T82-L91, BLIMPS_PRINTS K46-N61, L70-Y81 EGF-like domain signature 1: C75-C86 MOTIFS EGF-like domain signature 2: C75-C86 MOTIFS 21 1838010CD1 174 S37 S73 S128 T46 N44 N55 N64 Signal Peptide: M1-G16, M1-E18 HMMER T118 Y68 Y94 Non-cytosolic domain: M1-R134 TMHMMER Transmembrane domain: T135-Y157 Cytosolic domain: R158-E174 Immunoglobulin domain: E42-Y98 HMMER_PFAM 22 1741076CD1 75 Signal_cleavage: M1-S21 SPSCAN Signal Peptide: M1-S19, M1-C16, HMMER M1-S21, M1-P23 Glycosyl hydrolases family 5 signature: PROFILESCAN E6-D62 23 2692031CD1 575 S66 S67 S250 S305 N566 Signal_cleavage: M1-A29 SPSCAN S379 T163 T262 Signal Peptide: M1-R32, K12-A29 HMMER Cytosolic domain: M1-K12 TMHMMER Transmembrane domain: R13-V30 Non-cytosolic domain: T31-P575 TonB-dependent receptor proteins signature MOTIFS 1: M1-L5 24 7237245CD1 327 S51 S64 S99 S113 N258 Signal_cleavage: M1-A48 SPSCAN S143 S147 S183 S217 S269 T105 T119 T155 T202 T204 T319 WD domain, G-beta repeat: L38-G74, HMMER_PFAM C116-V152, K157-D193, C241-N280, I286-K324, D75-D110 Trp-Asp (WD-40) repeats signature: PROFILESCAN S87-C129, S50-L96, S169-A301, F256-A301 G-protein beta WD-40 repeat signature BLIMPS_PRINTS PR00320: I180-T194, I267-L281 Trp-Asp (WD) repeat protein BL00678: BLIMPS_BLOCKS S63-W73 Trp-Asp (WD) repeats signature: MOTIFS I180-T194, I267-L281 25 7488021CD1 115 S69 S91 T85 Signal_cleavage: M1-R51 SPSCAN Signal peptide: M32-A49 HMMER TAXOL RESISTANT ASSOCIATED PROTEIN BLAST_PRODOM PD173502: M1-P115 26 7390973CD1 311 S10 S126 S235 N102 N139 N224 signal_cleavage: M1-P34 SPSCAN Y113 Signal Peptide: M1-P34 HMMER Immunoglobulin domain: G52-F135 HMMER_PFAM BUTYROPHILIN PRECURSOR SIGNAL BLAST_PRODOM IMMUNOGLOBULIN PROTEIN TRANSMEMBRANE GLYCOPROTEIN FOLD MYELIN OLIGODENDROCYTE MYELIN PD000570: V40-C133 BUTYROPHILIN PRECURSOR BT BLAST_PRODOM TRANSMEMBRANE GLYCOPROTEIN IMMUNOGLOBULIN FOLD SIGNAL PROTEIN BTF4 PD004895: D138-V216 ANTIGEN; V-REGION-LIKE; B-G; BLAST_DOMO DM02854|A47712|1-83: S10-E91 Non-cytosolic domain: M1-S257 TMHMMER Transmembrane domain: A258-L277 Cytosolic domain: R278-K311 27 4890777CD1 106 S54 S77 S94 T32 signal_cleavage: M1-A26 SPSCAN T90 Signal Peptide: M1-S25 HMMER 28 5511444CD1 121 T75 T111 signal_cleavage: M16-A70 SPSCAN Signal Peptide: M16-S35 HMMER Signal Peptide: M16-C39 HMMER Signal Peptide: M16-T38 HMMER 29 6104370CD1 102 S66 T12 T23 signal_cleavage: M1-S68 SPSCAN Signal Peptide: M45-A70 HMMER Signal Peptide: M45-S68 HMMER Signal Peptide: M45-T72 HMMER Aminoacyl-transfer RNA synthetases PROFILESCAN class-I signature: K4-L57 30 7488468CD1 79 S7 signal_cleavage: M1-A56 SPSCAN 31 7503555CD1 534 S66 S67 S250 S305 N525 signal_cleavage: M1-A29 SPSCAN S379 T163 T262 Signal Peptide: M1-R32 HMMER Cytosolic domain: M1-K12 TMHMMER Transmembrane domain: R13-V30 Non-cytosolic domain: T31-P534 TonB-dependent receptor proteins MOTIFS signature 1: M1-L5

[0397] TABLE 4 Polynucleotide SEQ ID NO:/ Incyte ID/ Sequence Length Sequence Fragments 32/7475736CB1/ 1-260, 1-278, 1-782, 83-719, 136-790, 286-965, 350-1044, 399-1035, 458-1148, 603-1200, 778-1399, 818-1428, 867- 2065 1440, 908-1542, 1008-1822, 1009-1864, 1014-1685, 1031-1531, 1043-1563, 1056-1731, 1058-1710, 1102-1710, 1115-1706, 1167-1433, 1517-2065 33/859872CB1/ 1-762, 12-792, 34-740, 34-973, 45-721, 85-756, 85-788, 91-730, 93-692, 94-484, 94-720, 94-743, 95-827, 96-651, 4812 105-430, 112-736, 120-530, 125-588, 294-3088, 316-873, 324-510, 349-565, 533-1204, 599-1124, 718-1427, 883- 1293, 1039-1568, 1058-1339, 1120-1242, 1152-1730, 1189-1435, 1242-1339, 1353-1931, 1356-1952, 1536-1736, 1605-2126, 1605-2326, 1638-2078, 1665-2304, 1687-2208, 1692-2326, 1707-1897, 1708-1979, 1725-2328, 1753- 2000, 1753-2023, 1759-2012, 1782-2433, 1805-2083, 1809-2420, 1811-1976, 1815-2078, 1865-2323, 1883-2461, 1890-2135, 1940-2527, 1961-2574, 1964-2346, 1971-2159, 2036-2297, 2043-2700, 2061-2145, 2062-2233, 2069- 2312, 2077-2331, 2081-2448, 2084-2670, 2106-2471, 2121-2402, 2128-2420, 2160-2421, 2164-2699, 2174-2278, 2194-2772, 2208-2471, 2208-2744, 2236-2664, 2241-2450, 2241-2590, 2241-2649, 2256-2668, 2279-2621, 2320- 2883, 2320-2896, 2352-2614, 2432-2693, 2435-2693, 2435-2709, 2435-2714, 2435-2716, 2435-2728, 2444-2862, 2452-2779, 2470-2883, 2475-2696, 2475-2713, 2475-2728, 2484-3155, 2564-2834, 2574-2856, 2593-2856, 2598-3192, 2603-2863, 2656-2940, 2657-2909, 2679-2914, 2685-3155, 2706-3285, 2707-3104, 2708-2991, 2709- 3038, 2718-3013, 2718-3032, 2747-2878, 2749-3041, 2752-3052, 2752-3374, 2756-3250, 2818-3235, 2822-3371, 2829-3367, 2850-3452, 2859-3344, 2866-3124, 2874-3344, 2877-3427, 2882-3346, 2894-3344, 2895-3344, 2910- 3365, 2917-3162, 2918-3355, 2931-3382, 2934-3371, 2937-3174, 2937-3382, 2940-3084, 2945-3370, 2948-3354, 2961-3212, 2992-3277, 2996-3407, 3001-3242, 3003-3370, 3010-3370, 3013-3239, 3013-3371, 3015-3352, 3036- 3367, 3048-3381, 3053-3370, 3055-3540, 3129-3364, 3164-3372, 3209-3650, 3236-3803, 3237-3479, 3249-3354, 3312-3686, 3333-3582, 3345-3592, 3346-3629, 3367-4032, 3368-3626, 3390-3534, 3390-3934, 3399-3691, 3418- 3689, 3459-3715, 3514-4109, 3515-3778, 3520-4031, 3545-3785, 3584-4165, 3628-3902, 3633-3893, 3638-3890, 3638-4221, 3694-4045, 3701-4221, 3705-3956, 3731-4225, 3748-4223, 3753-4223, 3759-4219, 3761-4131, 3765- 4022, 3765-4216, 3767-4219, 3769-4219, 3769-4224, 3773-4227, 3784-3922, 3787-4225, 3792-4225, 3793-4217, 3807-4219, 3811-4224, 3822-4224, 3849-4224, 3873-4227, 3877-4223, 3888-4219, 3915-4171, 3945-4421, 3947-4421, 3948-4159, 3950-4225, 3952-4093, 3959-4462, 3965-4094, 3986-4225, 3987-4225, 4010-4437, 4020- 4221, 4026-4224, 4027-4222, 4027-4224, 4030-4722, 4033-4306, 4066-4224, 4078-4812, 4236-4516, 4236-4695, 4236-4721 34/1893683CB1/ 1-280, 1-502, 1-503, 1-971, 29-256, 31-293, 35-503, 81-503, 89-712, 89-884, 148-360, 216-445, 222-424, 222-494, 971 312-570, 321-971, 503-876 35/2824347CB1/ 1-385, 101-553, 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1130-1462, 1194-1826, 1198-1896, 1208-1708, 1243-2004, 1249-1640, 1250- 1672, 1250-1861, 1250-1943, 1250-1953, 1250-2051, 1250-2105, 1251-1401, 1251-1537, 1251-1602, 1251-1699, 1251-1728, 1251-1778, 1251-1791, 1251-1806, 1251-1823, 1251-1835, 1251-1860, 1251-1874, 1251-1884, 1251- 1965, 1251-1970, 1251-1973, 1251-1978, 1251-1984, 1251-1986, 1251-1991, 1251-2002, 1251-2011, 1251-2057, 1251-2107, 1252-2076, 1253-1908, 1254-2000, 1257-1829, 1258-2099, 1291-1984, 1294-1982, 1352-2004, 1381- 2270, 1385-1704, 1405-2279, 1415-2158, 1433-1825, 1442-2266, 1467-2060, 1473-2094, 1474-2010, 1480-2004, 1481-2254, 1492-2053, 1557-2097, 1562-1917, 1610-2076, 1613-2075, 1646-2063, 1649-2046, 1669-2229, 1703- 2201, 1723-2121, 1731-2426, 1732-2238, 1758-2410, 1776-1938, 1782-1937, 1786-2038, 1793-2059, 1834-2064, 1834-2609, 1835-2472, 1836-2622, 1840-2582, 1847-2544, 1852-2547, 1872-2622, 1933-2352 49/7486351CB1/ 1-1350, 476-951, 944-1395, 1202-1636 1636 50/1709023CB1/ 1-273, 1-629, 1-669, 1-792, 14-513, 46-717, 48-273, 48-302, 48-569, 93-538, 96-735, 146-398, 146-657, 201-880, 943 277-814, 277-862, 287-943, 322-618 51/1556012CB1/ 1-207, 1-407, 1-584, 1-826, 158-827, 160-734 827 52/1838010CB1/ 1-212, 1-223, 1-228, 1-256, 1-571, 46-293, 139-417, 192-417, 325-531, 325-776, 349-595, 360-612, 384-988, 640- 988 867, 673-805, 686-985 53/1741076CB1/ 1-268, 1-414, 1-575, 1-666, 1-780, 4-236, 121-752, 175-783 783 54/2692031CB1/ 1-643, 1-655, 1-709, 1-775, 1-836, 8-855, 40-705, 51-891, 52-704, 58-629, 117-850, 122-954, 148-996, 177-1023, 2974 209-1028, 211-966, 211-1015, 227-1051, 256-1074, 282-1076, 286-1016, 288-1123, 339-1102, 375-790, 375-813, 499-1321, 503-1349, 568-826, 568-1060, 568-1113, 668-935, 668-946, 668-1216, 675-1142, 680-862, 686-1194, 736-1154, 802-1400, 837-1474, 950-1099, 1044-1654, 1069-1678, 1097-1705, 1157-1822, 1171-1467, 1206-1694, 1224-1834, 1243-1839, 1263-1798, 1291-1513, 1291-1663, 1291-1707, 1291-1726, 1291-1731, 1291-1809, 1291- 1822, 1291-1845, 1291-1868, 1291-1886, 1293-1803, 1309-1892, 1319-1552, 1321-1956, 1335-1590, 1335-1815, 1337-1576, 1351-1693, 1364-1937, 1370-1951, 1377-2088, 1385-1891, 1385-2028, 1393-1584, 1403-1943, 1433- 2121, 1475-2117, 1567-2051, 1604-2268, 1622-2249, 1635-2148, 1657-2213, 1690-2247, 1757-2263, 1774-2293, 1783-2359, 1790-2384, 1835-2233, 1861-2262, 1886-2416, 1887-2090, 1945-2497, 1951-2417, 1977-2348, 1999- 2619, 2019-2275, 2019-2386, 2019-2425, 2196-2425, 2352-2646, 2424-2615, 2442-2974 55/7237245CB1/ 1-732, 1-1939, 36-874, 36-894, 36-902, 380-1254, 400-1254, 450-1254, 553-1254, 622-1254, 714-936, 742-1266, 1939 751-864, 782-936, 942-1162, 1105-1406, 1164-1298, 1228-1438, 1228-1830, 1484-1919 56/7488021CB1/ 1-815 815 57/7390973CB1/ 1-286, 1-1278, 12-531, 29-274, 29-285, 76-708, 168-439, 168-600, 264-669, 276-533, 279-870, 462-1058, 605-906, 1278 615-906, 759-906, 774-1023, 786-1068, 786-1077 58/4890777CB1/ 1-194, 1-277, 1-623, 1-901, 297-875 901 59/5511444CB1/ 1-172, 1-215, 1-263, 1-265, 1-523, 1-717, 5-608, 178-756, 322-976, 404-975, 461-976, 470-976, 539-976, 555-976, 976 624-793, 668-973 60/6104370CB1/ 1-389, 1-745, 130-673, 132-444, 132-453, 132-668, 132-669, 132-685, 132-691, 132-709, 132-770, 138-761, 172- 2054 816, 248-775, 373-622, 389-847, 483-761, 534-850, 544-710, 619-900, 687-1194, 695-1205, 703-1194, 747-1433, 765-1223, 888-1335, 891-1524, 901-1474, 951-1154, 1014-1682, 1022-1652, 1071-1692, 1221-1692, 1259-1690, 1263-1690, 1351-1587, 1608-2054, 1632-1942 61/7488468CB1/ 1-240, 161-537, 208-610 610 62/7503555CB1/ 1-536, 1-537, 1-543, 1-560, 1-577, 1-597, 1-633, 1-654, 1-674, 1-675, 1-701, 1-710, 1-2852, 26-648, 26-717, 26-818, 2852 26-829, 26-902, 26-957, 29-735, 34-431, 47-778, 148-997, 276-1017, 504-1350, 569-827, 569-1067, 569-1115, 669- 936, 669-948, 669-1217, 669-1284, 669-1388, 669-1440, 673-1197, 675-786, 676-1143, 681-889, 682-1310, 700- 1322, 800-1401, 928-1131, 928-1555, 957-1570, 986-1284, 1009-1160, 1101-1506, 1107-1234, 1147-1406, 1172- 1473, 1228-1489, 1255-1473, 1292-1508, 1292-1514, 1320-1566, 1336-1587, 1338-1589, 1338-1991, 1340-1530, 1583-1994, 1583-2125, 1583-2282, 1583-2283, 1583-2284, 1593-2263, 1607-1799, 1629-2141, 1652-2172, 1656- 1973, 1661-2237, 1668-2284, 1672-2200, 1689-2133, 1689-2141, 1690-1855, 1696-2254, 1700-2304, 1739-2215, 1752-2294, 1763-2294, 1764-2229, 1765-1968, 1766-2304, 1786-2168, 1805-2294, 1819-2259, 1825-2375, 1829- 2296, 1850-2155, 1855-2210, 1859-2302, 1864-2297, 1883-2540, 1897-2154, 1897-2291, 1897-2304, 1919-2297, 1927-2279, 1932-2303, 2011-2185, 2051-2283, 2075-2304, 2100-2232, 2187-2524, 2209-2581, 2251-2521, 2302- 2498, 2320-2852

[0398] TABLE 5 Polynucleotide Incyte Representative SEQ ID NO: Project ID: Library 32 7475736CB1 LUNGNON03 33 859872CB1 BRAYDIN03 34 1893683CB1 BRAIFEN08 35 2824347CB1 ADRETUT06 36 5055878CB1 COLENOR03 38 7497718CB1 PROSTUT09 39 7498077CB1 SINTFER02 40 1633319CB1 SPLNNOT02 41 1712631CB1 PROSTUT09 42 1795426CB1 OSTEUNC01 43 1329584CB1 PANCNOT07 44 3592659CB1 293TF5T01 45 7596081CB1 BRAITDR03 46 3009869CB1 HEARNOT01 47 7349094CB1 BRACNOK02 48 6826956CB1 SINTNOR01 50 1709023CB1 PROSNOT16 51 1556012CB1 BLADTUT04 52 1838010CB1 BRAVUNT02 53 1741076CB1 HIPONON01 54 2692031CB1 OVARNON03 55 7237245CB1 BRAYDIN03 57 7390973CB1 UTRSNOT08 58 4890777CB1 PROSTMT05 59 5511444CB1 BRADDIR01 60 6104370CB1 THP1T7T01 62 7503555CB1 OVARNON03

[0399] TABLE 6 Library Vector Library Description 293TF5T01 pINCY Library was constructed using RNA isolated from a transformed embryonal cell line (293-EBNA) derived from kidney epithelial tissue transfected with bga1. The cells were transformed with adenovirus 5 DNA. ADRETUT06 pINCY Library was constructed using RNA isolated from adrenal tumor tissue removed from a 57-year- old Caucasian female during a unilateral right adrenalectomy. Pathology indicated pheochromocytoma, forming a nodular mass completely replacing the medulla of the adrenal gland. BLADTUT04 pINCY Library was constructed using RNA isolated from bladder tumor tissue removed from a 60-year- old Caucasian male during a radical cystectomy, prostatectomy, and vasectomy. Pathology indicated grade 3 transitional cell carcinoma in the left bladder wall. Carcinoma in-situ was identified in the dome and trigone. Patient history included tobacco use. Family history included type I diabetes, malignant neoplasm of the stomach, atherosclerotic coronary artery disease, and acute myocardial infarction. BRACNOK02 PSPORT1 This amplified and normalized library was constructed using RNA isolated from posterior cingulate tissue removed from an 85-year-old Caucasian female who died from myocardial infarction and retroperitoneal hemorrhage. Pathology indicated atherosclerosis, moderate to severe, involving the circle of Willis, middle cerebral, basilar and vertebral arteries; infarction, remote, left dentate nucleus; and amyloid plaque deposition consistent with age. There was mild to moderate leptomeningeal fibrosis, especially over the convexity of the frontal lobe. There was mild generalized atrophy involving all lobes. The white matter was mildly thinned. Cortical thickness in the temporal lobes, both maximal and minimal, was slightly reduced. The substantia nigra pars compacta appeared mildly depigmented. Patient history included COPD, hypertension, and recurrent deep venous thrombosis. 6.4 million independent clones from this amplified library were normalized in one round using conditions adapted from Soares et al., PNAS (1994) 91: 9228-9232 and Bonaldo et al., Genome Research 6 (1996): 791. BRADDIR01 pINCY Library was constructed using RNA isolated from diseased choroid plexus tissue of the lateral ventricle, removed from the brain of a 57-year-old Caucasian male, who died from a cerebrovascular accident BRAIFEN08 pINCY This normalized fetal brain tissue library was constructed from 400 thousand independent clones from a fetal brain tissue library. Starting RNA was made from brain tissue removed from a Caucasian male fetus who was stillborn with a hypoplastic left heart at 23 weeks' gestation. The library was normalized in 2 rounds using conditions adapted from Soares et al., PNAS (1994) 91: 9228 and Bonaldo et al., Genome Research (1996) 6: 791, except that a significantly longer (48 hours/round) reannealing hybridization was used. BRAITDR03 PCDNA2.1 This random primed library was constructed using RNA isolated from allocortex, cingulate posterior tissue removed from a 55-year-old Caucasian female who died from cholangiocarcinoma. Pathology indicated mild meningeal fibrosis predominately over the convexities, scattered axonal spheroids in the white matter of the cingulate cortex and the thalamus, and a few scattered neurofibrillary tangles in the entorhinal cortex and the periaqueductal gray region. Pathology for the associated tumor tissue indicated well-differentiated cholangiocarcinoma of the liver with residual or relapsed tumor. Patient history included cholangiocarcinoma, post- operative Budd-Chiari syndrome, biliary ascites, hydrothorax, dehydration, malnutrition, oliguria and acute renal failure. Previous surgeries included cholecystectomy and resection of 85% of the liver. BRAVUNT02 PSPORT1 Library was constructed using pooled RNA isolated from separate populations of unstimulated astrocytes. BRAYDIN03 pINCY This normalized library was constructed from 6.7 million independent clones from a brain tissue library. Starting RNA was made from RNA isolated from diseased hypothalamus tissue removed from a 57-year-old Caucasian male who died from a cerebrovascular accident. Patient history included Huntington's disease and emphysema. The library was normalized in 2 rounds using conditions adapted from Soares et al., PNAS (1994) 91: 9228 and Bonaldo et al., Genome Research (1996) 6: 791, except that a significantly longer (48-hours/round) reannealing hybridization was used. The library was linearized and recircularized to select for insert containing clones. COLENOR03 PCDNA2.1 Library was constructed using RNA isolated from colon epithelium tissue removed from a 13- year-old Caucasian female who died from a motor vehicle accident HEARNOT01 PBLUESCRIPT Library was constructed using RNA isolated from the whole heart tissue of a 56-year-old male, who died from an intracranial bleed. HIPONON01 PSPORT1 This normalized hippocampus library was constructed from 1.13M independent clones from a hippocampus tissue library. RNA was isolated from the hippocampus tissue of a 72-year-old Caucasian female who died from an intracranial bleed. Patient history included nose cancer, hypertension, and arthritis. The normalization and hybridization conditions were adapted from Soares et al. (PNAS (1994) 91: 9228). LUNGNON03 PSPORT1 This normalized library was constructed from 2.56 million independent clones from a lung tissue library. RNA was made from lung tissue removed from the left lobe of a 58-year-old Caucasian male during a segmental lung resection. Pathology for the associated tumor tissue indicated a metastatic grade 3 (of 4) osteosarcoma. Patient history included soft tissue cancer, secondary cancer of the lung, prostate cancer, and an acute duodenal ulcer with hemorrhage. Patient also received radiation therapy to the retroperitoneum. Family history included prostate cancer, breast cancer, and acute leukemia. The normalization and hybridization conditions were adapted from Soares et al., PNAS (1994) 91: 9228; Swaroop et al., NAR (1991) 19: 1954; and Bonaldo et al., Genome Research (1996) 6: 791. OSTEUNC01 pINCY This large size-fractionated library was constructed using RNA isolated from untreated osteoblast tissue removed from the clavicle of a 40-year-old male. OVARNON03 pINCY This normalized ovarian tissue library was constructed from 5 million independent clones from an ovary library. Starting RNA was made from ovarian tissue removed from a 36-year-old Caucasian female during total abdominal hysterectomy, bilateral salpingo-oophorectomy, soft tissue excision, and an incidental appendectomy. Pathology for the associated tumor tissue indicated one intramural and one subserosal leiomyomata of the myometrium. The endometrium was proliferative phase. Patient history included deficiency anemia, calculus of the kidney, and a kidney anomaly. Family history included hyperlipidemia, acute myocardial infarction, atherosclerotic coronary artery disease, type II diabetes, and chronic liver disease. The library was normalized in two rounds using conditions adapted from Soares et al., PNAS (1994) 91: 9228 and Bonaldo et al., Genome Research (1996) 6: 791, except that a significantly longer (48 hours/round) reannealing hybridization was used. PANCNOT07 pINCY Library was constructed using RNA isolated from the pancreatic tissue of a Caucasian male fetus, who died at 23 weeks' gestation. PROSNOT16 pINCY Library was constructed using RNA isolated from diseased prostate tissue removed from a 68- year-old Caucasian male during a radical prostatectomy. Pathology indicated adenofibromatous hyperplasia. Pathology for the associated tumor tissue indicated an adenocarcinoma (Gleason grade 3 + 4). The patient presented with elevated prostate specific antigen (PSA). During this hospitalization, the patient was diagnosed with myasthenia gravis. Patient history included osteoarthritis, and type II diabetes. Family history included benign hypertension, acute myocardial infarction, hyperlipidemia, and arteriosclerotic coronary artery disease. PROSTMT05 pINCY The library was constructed using RNA isolated from diseased prostate tissue removed from a 55-year-old Caucasian male during a radical prostatectomy, regional lymph node excision, and prostate needle biopsy. Pathology indicated adenofibromatous hyperplasia. Pathology for the associated tumor tissue indicated adenocarcinoma, Gleason grade 5 + 4, forming a predominant mass involving the left side peripherally with extension into the right posterior superior region. The tumor invaded and perforated the capsule to involve periprostatic tissue in the left posterior superior region. The left inferior and superior posterior surgical margins were positive. One (of 9) left pelvic lymph nodes was metastatically involved. The patient presented with elevated prostate specific antigen (PSA). Patient history included calculus of the kidney. Family history included breast cancer and lung cancer. PROSTUT09 pINCY Library was constructed using RNA isolated from prostate tumor tissue removed from a 66-year- old Caucasian male during a radical prostatectomy, radical cystectomy, and urinary diversion. Pathology indicated grade 3 transitional cell carcinoma. The patient presented with prostatic inflammatory disease. Patient history included lung neoplasm, and benign hypertension. Family history included a malignant breast neoplasm, tuberculosis, cerebrovascular disease, atherosclerotic coronary artery disease and lung cancer. SINTFER02 pINCY This random primed library was constructed using RNA isolated from small intestine tissue removed from a Caucasian male fetus who died from fetal demise. SINTNOR01 PCDNA2.1 This random primed library was constructed using RNA isolated from small intestine tissue removed from a 31-year-old Caucasian female during Roux-en-Y gastric bypass. Patient history included clinical obesity. SPLNNOT02 PBLUESCRIPT Library was constructed using RNA isolated from the spleen tissue of a 29-year-old Caucasian male, who died from head trauma. Serologies were positive for cytomegalovirus (CMV) but otherwise negative. Patient history included alcohol, marijuana, and tobacco use. THP1T7T01 pINCY Library was constructed using RNA isolated from 50,000 cultured THP-1 cells, which was amplified using a proprietary T7 amplification method developed at Incyte. THP-1 is a human promonocyte line derived from the peripheral blood of a 1-year-old Caucasian male with acute monocytic leukemia (ref: Int. J. Cancer (1980) 26: 171). UTRSNOT08 pINCY Library was constructed using RNA isolated from uterine tissue removed from a 35-year-old Caucasian female during a vaginal hysterectomy with dilation and curettage. Pathology indicated that the endometrium was secretory phase with a benign endometrial polyp 1 cm in diameter. The cervix showed mild chronic cervicitis. Family history included atherosclerotic coronary artery disease and type II diabetes.

[0400] TABLE 7 Program Description Reference Parameter Threshold ABI FACTURA A program that removes vector sequences and masks Applied Biosystems, ambiguous bases in nucleic acid sequences. Foster City, CA. ABI/ A Fast Data Finder useful in comparing and Applied Biosystems, Mismatch <50% PARACEL FDF annotating amino acid or nucleic acid sequences. Foster City, CA; Paracel Inc., Pasadena, CA. ABI A program that assembles nucleic acid sequences. Applied Biosystems, AutoAssembler Foster City, CA. BLAST A Basic Local Alignment Search Tool useful in Altschul, S. F. et al. ESTs: Probability sequence similarity search for amino acid and nucleic (1990) J. Mol. Biol. value = 1.0E−8 acid sequences. BLAST includes five functions: 215: 403-410; or less; Full blastp, blastn, blastx, tblastn, and tblastx. Altschul, S. F. et al. Length sequences: (1997) Nucleic Acids Probability value = Res. 25: 3389-3402. 1.0E−10 or less FASTA A Pearson and Lipman algorithm that searches for Pearson, W. R. and D. J. ESTs: fasta E similarity between a query sequence and a group of Lipman (1988) Proc. Natl. value = 1.06E−6; sequences of the same type. FASTA comprises as Acad Sci. USA 85: 2444-2448; Assembled ESTs: least five functions: fasta, tfasta, fastx, tfastx, Pearson, W. R. (1990) Methods fasta Identity = and ssearch. Enzymol. 183: 63-98; and 95% or greater Smith, T. F. and M. S. and Match length = Waterman (1981) Adv. Appl. 200 bases or greater; Math. 2: 482-489. fastx E value = 1.0E−8 or less; Full Length sequences: fastx score = 100 or greater BLIMPS A BLocks IMProved Searcher that matches a Henikoff, S. and J. G. Probability value = sequence against those in BLOCKS, PRINTS, Henikoff (1991) Nucleic 1.0E−3 or less DOMO, PRODOM, and PFAM databases to search Acids Res. 19: 6565-6572; for gene families, sequence homology, and Henikoff, J. G. and S. structural fingerprint regions. Henikoff (1996) Methods Enzymol. 266: 88-105; and Attwood, T. K. et al. (1997) J. Chem. Inf. Comput. Sci. 37: 417-424. HMMER An algorithm for searching a query sequence against Krogh, A. et al. (1994) J. PFAM, INCY, SMART hidden Markov model (HMM)-based databases of Mol. Biol. 235: 1501-1531; or TIGRFAM hits: protein family consensus sequences, such as PFAM, Sonnhammer, E. L. L. et al. Probability value = INCY, SMART and TIGRFAM. (1988) Nucleic Acids Res. 26: 1.0E−3 or less; 320-322; Durbin, R. et al. Signal peptide (1998) Our World View, in hits: Score = 0 a Nutshell, Cambridge Univ. or greater Press, pp. 1-350. ProfileScan An algorithm that searches for structural and Gribskov, M. et al. (1988) Normalized quality sequence motifs in protein sequences that match CABIOS 4: 61-66; Gribskov, score ≧ GCG sequence patterns defined in Prosite. M. et al. (1989) Methods specified “HIGH” Enzymol. 183: 146-159; value for that Bairoch, A. et al. (1997) particular Prosite Nucleic Acids Res. 25: motif. Generally, 217-221. score = 1.4-2.1. Phred A base-calling algorithm that examines automated Ewing, B. et al. (1998) sequencer traces with high sensitivity and probability. Genome Res. 8: 175-185; Ewing, B. and P. Green (1998) Genome Res. 8: 186-194. Phrap A Phils Revised Assembly Program including Smith, T. F. and M. S. Score = 120 SWAT and CrossMatch, programs based on efficient Waterman (1981) Adv. Appl. or greater; Match implementation of the Smith-Waterman algorithm, Math. 2: 482-489; length = 56 useful in searching sequence homology and Smith, T. F. and M. S. or greater assembling DNA sequences. Waterman (1981) J. Mol. Biol. 147: 195-197; and Green, P., University of Washington, Seattle, WA. Consed A graphical tool for viewing and editing Phrap Gordon, D. et al. (1998) assemblies. Genome Res. 8: 195-202. SPScan A weight matrix analysis program that scans protein Nielson, H. et al. (1997) Score = 3.5 sequences for the presence of secretory signal Protein Engineering 10: or greater peptides. 1-6; Claverie, J. M. and S. Audic (1997) CABIOS 12: 431-439. TMAP A program that uses weight matrices to delineate Persson, B. and P. Argos transmembrane segments on protein sequences and (1994) J. Mol. Biol. determine orientation. 237: 182-192; Persson, B. and P. Argos (1996) Protein Sci. 5: 363-371. TMHMMER A program that uses a hidden Markov model (HMM) Sonnhammer, E. L. et al. to delineate transmembrane segments on protein (1998) Proc. Sixth Intl. sequences and determine orientation. Conf. On Intelligent Systems for Mol. Biol., Glasgow et al., eds., The Am. Assoc. for Artificial Intelligence (AAAI) Press, Menlo Park, CA, and MIT Press, Cam- bridge, MA, pp. 175-182. Motifs A program that searches amino acid sequences for Bairoch, A. et al. (1997) patterns that matched those defined in Prosite. Nucleic Acids Res. 25: 217-221; Wisconsin Package Program Manual, version 9, page M51-59, Genetics Computer Group, Madison, WI.

[0401]

1 62 1 403 PRT Homo sapiens misc_feature Incyte ID No 7475736CD1 1 Met Cys Ala Pro Ala Ala Gly Ser Ser Gly Pro Phe Ser Ala Ser 1 5 10 15 Leu Ser Leu Ser Gln Leu Pro Gly Val Cys Gln Ser Asp Gln Ser 20 25 30 Thr Thr Leu Gly Ala Ser His Pro Pro Cys Phe Asn Arg Ser Thr 35 40 45 Tyr Ala Gln Gly Thr Thr Val Ala Pro Ser Ala Ala Pro Ala Thr 50 55 60 Arg Pro Ala Gly Asp Gln Gln Ser Val Ser Lys Ala Pro Asn Val 65 70 75 Gly Ser Arg Thr Ile Ala Ala Trp Pro His Ser Asp Ala Arg Glu 80 85 90 Gly Thr Ala Pro Ser Thr Thr Asn Ser Val Ala Gly His Ser Asn 95 100 105 Ser Ser Val Phe Pro Arg Ala Ala Ser Thr Thr Arg Thr Gln His 110 115 120 Arg Gly Glu His Ala Pro Glu Leu Val Leu Glu Pro Asp Ile Ser 125 130 135 Ala Ala Ser Thr Pro Leu Ala Ser Lys Leu Leu Gly Pro Phe Pro 140 145 150 Thr Ser Trp Asp Arg Ser Ile Ser Ser Pro Gln Pro Gly Gln Arg 155 160 165 Thr His Ala Thr Pro Gln Ala Pro Asn Pro Ser Leu Ser Glu Gly 170 175 180 Glu Ile Pro Val Leu Leu Leu Asp Asp Tyr Ser Glu Glu Glu Glu 185 190 195 Gly Arg Lys Glu Glu Val Gly Thr Pro His Gln Asp Val Pro Cys 200 205 210 Asp Tyr His Pro Cys Lys His Leu Gln Thr Pro Cys Ala Glu Leu 215 220 225 Gln Arg Arg Trp Arg Cys Arg Cys Pro Gly Leu Ser Gly Glu Asp 230 235 240 Thr Ile Pro Asp Pro Pro Arg Leu Gln Gly Val Thr Glu Thr Thr 245 250 255 Asp Thr Ser Ala Leu Val His Trp Cys Ala Pro Asn Ser Val Val 260 265 270 His Gly Tyr Gln Ile Arg Tyr Ser Ala Glu Gly Trp Ala Gly Asn 275 280 285 Gln Ser Val Val Gly Val Ile Tyr Ala Thr Ala Arg Gln His Pro 290 295 300 Leu Tyr Gly Leu Ser Pro Gly Thr Thr Tyr Arg Val Cys Val Leu 305 310 315 Ala Ala Asn Arg Ala Gly Leu Ser Gln Pro Arg Ser Ser Gly Trp 320 325 330 Arg Ser Pro Cys Ala Ala Phe Thr Thr Lys Pro Ser Phe Ala Leu 335 340 345 Leu Leu Ser Gly Leu Cys Ala Ala Ser Gly Leu Leu Leu Ala Ser 350 355 360 Thr Val Val Leu Ser Ala Cys Leu Cys Arg Arg Gly Gln Thr Leu 365 370 375 Gly Leu Gln Arg Cys Asp Thr His Leu Val Ala Tyr Lys Asn Pro 380 385 390 Ala Phe Asp Asp Tyr Pro Leu Gly Leu Gln Thr Val Ser 395 400 2 993 PRT Homo sapiens misc_feature Incyte ID No 859872CD1 2 Met Ala Ala Glu Trp Ala Ser Arg Phe Trp Leu Trp Ala Thr Leu 1 5 10 15 Leu Ile Pro Ala Ala Ala Val Tyr Glu Asp Gln Val Gly Lys Phe 20 25 30 Asp Trp Arg Gln Gln Tyr Val Gly Lys Val Lys Phe Ala Ser Leu 35 40 45 Glu Phe Ser Pro Gly Ser Lys Lys Leu Val Val Ala Thr Glu Lys 50 55 60 Asn Val Ile Ala Ala Leu Asn Ser Arg Thr Gly Glu Ile Leu Trp 65 70 75 Arg His Val Asp Lys Gly Thr Ala Glu Gly Ala Val Asp Ala Met 80 85 90 Leu Leu His Gly Gln Asp Val Ile Thr Val Ser Asn Gly Gly Arg 95 100 105 Ile Met Arg Ser Trp Glu Thr Asn Ile Gly Gly Leu Asn Trp Glu 110 115 120 Ile Thr Leu Asp Ser Gly Ser Phe Gln Ala Leu Gly Leu Val Gly 125 130 135 Leu Gln Glu Ser Val Arg Tyr Ile Ala Val Leu Lys Lys Thr Thr 140 145 150 Leu Ala Leu His His Leu Ser Ser Gly His Leu Lys Trp Val Glu 155 160 165 His Leu Pro Glu Ser Asp Ser Ile His Tyr Gln Met Val Tyr Ser 170 175 180 Tyr Gly Ser Gly Val Val Trp Ala Leu Gly Val Val Pro Phe Ser 185 190 195 His Val Asn Ile Val Lys Phe Asn Val Glu Asp Gly Glu Ile Val 200 205 210 Gln Gln Val Arg Val Ser Thr Pro Trp Leu Gln His Leu Ser Gly 215 220 225 Ala Cys Gly Val Val Asp Glu Ala Val Leu Val Cys Pro Asp Pro 230 235 240 Ser Ser Arg Ser Leu Gln Thr Leu Ala Leu Glu Thr Glu Trp Glu 245 250 255 Leu Arg Gln Ile Pro Leu Gln Ser Leu Asp Leu Glu Phe Gly Ser 260 265 270 Gly Phe Gln Pro Arg Val Leu Pro Thr Gln Pro Asn Pro Val Asp 275 280 285 Ala Ser Arg Ala Gln Phe Phe Leu His Leu Ser Pro Ser His Tyr 290 295 300 Ala Leu Leu Gln Tyr His Tyr Gly Thr Leu Ser Leu Leu Lys Asn 305 310 315 Phe Pro Gln Thr Ala Leu Val Ser Phe Ala Thr Thr Gly Glu Lys 320 325 330 Thr Val Ala Ala Val Met Ala Cys Arg Asn Glu Val Gln Lys Ser 335 340 345 Ser Ser Ser Glu Asp Gly Ser Met Gly Ser Phe Ser Glu Lys Ser 350 355 360 Ser Ser Lys Asp Ser Leu Ala Cys Phe Asn Gln Thr Tyr Thr Ile 365 370 375 Asn Leu Tyr Leu Val Glu Thr Gly Arg Arg Leu Leu Asp Thr Thr 380 385 390 Ile Thr Phe Ser Leu Glu Gln Ser Gly Thr Arg Pro Glu Arg Leu 395 400 405 Tyr Ile Gln Val Phe Leu Lys Lys Asp Asp Ser Val Gly Tyr Arg 410 415 420 Ala Leu Val Gln Thr Glu Asp His Leu Leu Leu Phe Leu Gln Gln 425 430 435 Leu Ala Gly Lys Val Val Leu Trp Ser Arg Glu Glu Ser Leu Ala 440 445 450 Glu Val Val Cys Leu Glu Met Val Asp Leu Pro Leu Thr Gly Ala 455 460 465 Gln Ala Glu Leu Glu Gly Glu Phe Gly Lys Lys Ala Asp Gly Leu 470 475 480 Leu Gly Met Phe Leu Lys Arg Leu Ser Ser Gln Leu Ile Leu Leu 485 490 495 Gln Ala Trp Thr Ser His Leu Trp Lys Met Phe Tyr Asp Ala Arg 500 505 510 Lys Pro Arg Ser Gln Ile Lys Asn Glu Ile Asn Ile Asp Thr Leu 515 520 525 Ala Arg Asp Glu Phe Asn Leu Gln Lys Met Met Val Met Val Thr 530 535 540 Ala Ser Gly Lys Leu Phe Gly Ile Glu Ser Ser Ser Gly Thr Ile 545 550 555 Leu Trp Lys Gln Tyr Leu Pro Asn Val Lys Pro Asp Ser Ser Phe 560 565 570 Lys Leu Met Val Gln Arg Thr Thr Ala His Phe Pro His Pro Pro 575 580 585 Gln Cys Thr Leu Leu Val Lys Asp Lys Glu Ser Gly Met Ser Ser 590 595 600 Leu Tyr Val Phe Asn Pro Ile Phe Gly Lys Trp Ser Gln Val Ala 605 610 615 Pro Pro Val Leu Lys Arg Pro Ile Leu Gln Ser Leu Leu Leu Pro 620 625 630 Val Met Asp Gln Asp Tyr Ala Lys Val Leu Leu Leu Ile Asp Asp 635 640 645 Glu Tyr Lys Val Thr Ala Phe Pro Ala Thr Arg Asn Val Leu Arg 650 655 660 Gln Leu His Glu Leu Ala Pro Ser Ile Phe Phe Tyr Leu Val Asp 665 670 675 Ala Glu Gln Gly Arg Leu Cys Gly Tyr Arg Leu Arg Lys Asp Leu 680 685 690 Thr Thr Glu Leu Ser Trp Glu Leu Thr Ile Pro Pro Glu Val Gln 695 700 705 Arg Ile Val Lys Val Lys Gly Lys Arg Ser Ser Glu His Val His 710 715 720 Ser Gln Gly Arg Val Met Gly Asp Arg Ser Val Leu Tyr Lys Ser 725 730 735 Leu Asn Pro Asn Leu Leu Ala Val Val Thr Glu Ser Thr Asp Ala 740 745 750 His His Glu Arg Thr Phe Ile Gly Ile Phe Leu Ile Asp Gly Val 755 760 765 Thr Gly Arg Ile Ile His Ser Ser Val Gln Lys Lys Ala Lys Gly 770 775 780 Pro Val His Ile Val His Ser Glu Asn Trp Val Val Tyr Gln Tyr 785 790 795 Trp Asn Thr Lys Ala Arg Arg Asn Glu Phe Thr Val Leu Glu Leu 800 805 810 Tyr Glu Gly Thr Glu Gln Tyr Asn Ala Thr Ala Phe Ser Ser Leu 815 820 825 Asp Arg Pro Gln Leu Pro Gln Val Leu Gln Gln Ser Tyr Ile Phe 830 835 840 Pro Ser Ser Ile Ser Ala Met Glu Ala Thr Ile Thr Glu Arg Gly 845 850 855 Ile Thr Ser Arg His Leu Leu Ile Gly Leu Pro Ser Gly Ala Ile 860 865 870 Leu Ser Leu Pro Lys Ala Leu Leu Asp Pro Arg Arg Pro Glu Ile 875 880 885 Pro Thr Glu Gln Ser Arg Glu Glu Asn Leu Ile Pro Tyr Ser Pro 890 895 900 Asp Val Gln Ile His Ala Glu Arg Phe Ile Asn Tyr Asn Gln Thr 905 910 915 Val Ser Arg Met Arg Gly Ile Tyr Thr Ala Pro Ser Gly Leu Glu 920 925 930 Ser Thr Cys Leu Val Val Ala Tyr Gly Leu Asp Ile Tyr Gln Thr 935 940 945 Arg Val Tyr Pro Ser Lys Gln Phe Asp Val Leu Lys Asp Asp Tyr 950 955 960 Asp Tyr Val Leu Ile Ser Ser Val Leu Phe Gly Leu Val Phe Ala 965 970 975 Thr Met Ile Thr Lys Arg Leu Ala Gln Val Lys Leu Leu Asn Arg 980 985 990 Ala Trp Arg 3 127 PRT Homo sapiens misc_feature Incyte ID No 1893683CD1 3 Met Ala Leu Val Pro Tyr Glu Glu Thr Thr Glu Phe Gly Leu Gln 1 5 10 15 Lys Phe His Lys Pro Leu Ala Thr Phe Ser Phe Ala Asn His Thr 20 25 30 Ile Gln Ile Arg Gln Asp Trp Arg His Leu Gly Val Ala Ala Val 35 40 45 Val Trp Asp Ala Ala Ile Val Leu Ser Thr Tyr Leu Glu Met Gly 50 55 60 Ala Val Glu Leu Arg Gly Arg Ser Ala Val Glu Leu Gly Ala Gly 65 70 75 Thr Gly Leu Val Gly Ile Val Ala Ala Leu Leu Glu Asn Thr Gly 80 85 90 Gln Met Gln Thr Glu Gly Tyr Ser Lys Arg Lys Gln Ile Thr Thr 95 100 105 Leu Gln Lys Leu Gln Gly His Gln Arg Gln Gly Asn Lys Leu Ser 110 115 120 Gln Thr Glu Gly Asp Tyr Asn 125 4 590 PRT Homo sapiens misc_feature Incyte ID No 2824347CD1 4 Met Gly Phe His Leu Ile Thr Gln Leu Lys Gly Met Ser Val Val 1 5 10 15 Leu Val Leu Leu Pro Thr Leu Leu Leu Val Met Leu Thr Gly Ala 20 25 30 Gln Arg Ala Cys Pro Lys Asn Cys Arg Cys Asp Gly Lys Ile Val 35 40 45 Tyr Cys Glu Ser His Ala Phe Ala Asp Ile Pro Glu Asn Ile Ser 50 55 60 Gly Gly Ser Gln Gly Leu Ser Leu Arg Phe Asn Ser Ile Gln Lys 65 70 75 Leu Lys Ser Asn Gln Phe Ala Gly Leu Asn Gln Leu Ile Trp Leu 80 85 90 Tyr Leu Asp His Asn Tyr Ile Ser Ser Val Asp Glu Asp Ala Phe 95 100 105 Gln Gly Ile Arg Arg Leu Lys Glu Leu Ile Leu Ser Ser Asn Lys 110 115 120 Ile Thr Tyr Leu His Asn Lys Thr Phe His Pro Val Pro Asn Leu 125 130 135 Arg Asn Leu Asp Leu Ser Tyr Asn Lys Leu Gln Thr Leu Gln Ser 140 145 150 Glu Gln Phe Lys Gly Leu Arg Lys Leu Ile Ile Leu His Leu Arg 155 160 165 Ser Asn Ser Leu Lys Thr Val Pro Ile Arg Val Phe Gln Asp Cys 170 175 180 Arg Asn Leu Asp Phe Leu Asp Leu Gly Tyr Asn Arg Leu Arg Ser 185 190 195 Leu Ser Arg Asn Ala Phe Ala Gly Leu Leu Lys Leu Lys Glu Leu 200 205 210 His Leu Glu His Asn Gln Phe Ser Lys Ile Asn Phe Ala His Phe 215 220 225 Pro Arg Leu Phe Asn Leu Arg Ser Ile Tyr Leu Gln Trp Asn Arg 230 235 240 Ile Arg Ser Ile Ser Gln Gly Leu Thr Trp Thr Trp Ser Ser Leu 245 250 255 His Asn Leu Asp Leu Ser Gly Asn Asp Ile Gln Gly Ile Glu Pro 260 265 270 Gly Thr Phe Lys Cys Leu Pro Asn Leu Gln Lys Leu Asn Leu Asp 275 280 285 Ser Asn Lys Leu Thr Asn Ile Ser Gln Glu Thr Val Asn Ala Trp 290 295 300 Ile Ser Leu Ile Ser Ile Thr Leu Ser Gly Asn Met Trp Glu Cys 305 310 315 Ser Arg Ser Ile Cys Pro Leu Phe Tyr Trp Leu Lys Asn Phe Lys 320 325 330 Gly Asn Lys Glu Ser Thr Met Ile Cys Ala Gly Pro Lys His Ile 335 340 345 Gln Gly Glu Lys Val Ser Asp Ala Val Glu Thr Tyr Asn Ile Cys 350 355 360 Ser Glu Val Gln Val Val Asn Thr Glu Arg Ser His Leu Val Pro 365 370 375 Gln Thr Pro Gln Lys Pro Leu Ile Ile Pro Arg Pro Thr Ile Phe 380 385 390 Lys Pro Asp Val Thr Gln Ser Thr Phe Glu Thr Pro Ser Pro Ser 395 400 405 Pro Gly Phe Gln Ile Pro Gly Ala Glu Gln Glu Tyr Glu His Val 410 415 420 Ser Phe His Lys Ile Ile Ala Gly Ser Val Ala Leu Phe Leu Ser 425 430 435 Val Ala Met Ile Leu Leu Val Ile Tyr Val Ser Trp Lys Arg Tyr 440 445 450 Pro Ala Ser Met Lys Gln Leu Gln Gln His Ser Leu Met Lys Arg 455 460 465 Arg Arg Lys Lys Ala Arg Glu Ser Glu Arg Gln Met Asn Ser Pro 470 475 480 Leu Gln Glu Tyr Tyr Val Asp Tyr Lys Pro Thr Asn Ser Glu Thr 485 490 495 Met Asp Ile Ser Val Asn Gly Ser Gly Pro Cys Thr Tyr Thr Ile 500 505 510 Ser Gly Ser Arg Glu Cys Glu Met Pro His His Met Lys Pro Leu 515 520 525 Pro Tyr Tyr Ser Tyr Asp Gln Pro Val Ile Gly Tyr Cys Gln Ala 530 535 540 His Gln Pro Leu His Val Thr Lys Gly Tyr Gly Thr Val Ser Pro 545 550 555 Glu Gln Asp Glu Ser Pro Gly Leu Glu Leu Gly Arg Asp His Ser 560 565 570 Phe Ile Ala Thr Ile Ala Arg Ser Ala Ala Pro Ala Ile Tyr Leu 575 580 585 Glu Arg Ile Ala Asn 590 5 262 PRT Homo sapiens misc_feature Incyte ID No 5055878CD1 5 Met Ala Trp Lys Ser Ser Val Ile Met Gln Met Gly Arg Phe Leu 1 5 10 15 Leu Leu Val Ile Leu Phe Leu Pro Arg Glu Met Thr Ser Ser Val 20 25 30 Leu Thr Val Asn Gly Lys Thr Glu Asn Tyr Ile Leu Asp Thr Thr 35 40 45 Pro Gly Ser Gln Ala Ser Leu Ile Cys Ala Val Gln Asn His Thr 50 55 60 Arg Glu Glu Glu Leu Leu Trp Tyr Arg Glu Glu Gly Arg Val Asp 65 70 75 Leu Lys Ser Gly Asn Lys Ile Asn Ser Ser Ser Val Cys Val Ser 80 85 90 Ser Ile Ser Glu Asn Asp Asn Gly Ile Ser Phe Thr Cys Arg Leu 95 100 105 Gly Arg Asp Gln Ser Val Ser Val Ser Val Val Leu Asn Val Thr 110 115 120 Phe Pro Pro Leu Leu Ser Gly Asn Asp Phe Gln Thr Val Glu Glu 125 130 135 Gly Ser Asn Val Lys Leu Val Cys Asn Val Lys Ala Asn Pro Gln 140 145 150 Ala Gln Met Met Trp Tyr Lys Asn Ser Ser Leu Leu Asp Leu Glu 155 160 165 Lys Ser Arg His Gln Ile Gln Gln Thr Ser Glu Ser Phe Gln Leu 170 175 180 Ser Ile Thr Lys Val Glu Lys Pro Asp Asn Gly Thr Tyr Ser Cys 185 190 195 Ile Ala Lys Ser Ser Leu Lys Thr Glu Ser Leu Asp Phe His Leu 200 205 210 Ile Val Lys Asp Lys Thr Val Gly Val Pro Ile Glu Pro Ile Ile 215 220 225 Ala Ala Cys Val Val Ile Phe Leu Thr Leu Cys Phe Gly Leu Ile 230 235 240 Ala Arg Arg Lys Lys Ile Met Lys Leu Cys Met Lys Asp Lys Asp 245 250 255 Pro His Ser Glu Thr Ala Leu 260 6 122 PRT Homo sapiens misc_feature Incyte ID No 7473596CD1 6 Met Asp Leu Ser Gln Leu Leu Gly Val Leu Leu Ala Glu Ser Ser 1 5 10 15 Ala Val Ser Pro Cys Arg Asp Cys Leu Ala Val Asp Ser Cys Gln 20 25 30 Gly His Ser Pro Ser Gln Val Gly Pro Gln Pro Val Met Glu Ala 35 40 45 Tyr Lys Gly Leu Thr Ile Ser Ala Gln Leu Arg Thr Asn Leu Lys 50 55 60 Gly His Ser Asn Ser Thr Asn Ser Arg Thr Ala Cys Gly Ser Ala 65 70 75 Lys Ala Val Thr Gly Pro Ser Phe Ala Ala Gln Tyr Leu Tyr Ile 80 85 90 Ser Cys Asn Lys Ser Asn Ala Ser Asn Val Ser His Phe Leu Gly 95 100 105 Ala Ala Ser Leu Ser Pro Val Ser Met Phe Gly Lys Arg Tyr Lys 110 115 120 Asp Thr 7 140 PRT Homo sapiens misc_feature Incyte ID No 7497718CD1 7 Met Asn Trp Val Ala Val Leu Cys Pro Leu Gly Ile Val Trp Met 1 5 10 15 Val Gly Asp Gln Pro Pro Gln Val Leu Ser Gln Ala Ser Ser Leu 20 25 30 Ala Val Tyr Leu Arg Ala Ala Pro Tyr Pro Asp Val Thr Ala Lys 35 40 45 Lys Leu Arg His Asp Thr Asn Cys Gly Phe Pro Arg Gln Gln Arg 50 55 60 Met Ala Arg Gly His Glu Gly Arg Ala Pro Leu Leu Asp Arg Pro 65 70 75 Thr Leu Lys Ser Arg Tyr Leu Arg Ala Asn His Lys Ile Asn Thr 80 85 90 Phe Glu Glu Ile Thr Ala Met Pro Ser Gln His Trp Val Pro Gly 95 100 105 Val Gly Leu Ala Cys Pro Pro Thr Pro Ser Ala Glu Glu Trp Leu 110 115 120 Thr Ser Gly His Pro Pro Gly Cys His Ser Leu Val Pro Gly Glu 125 130 135 Ala Asn Val Leu Ala 140 8 776 PRT Homo sapiens misc_feature Incyte ID No 7498077CD1 8 Met Pro Val Pro Trp Phe Leu Leu Ser Leu Ala Leu Gly Arg Ser 1 5 10 15 Pro Val Val Leu Ser Leu Glu Arg Leu Val Gly Pro Gln Asp Ala 20 25 30 Thr His Cys Ser Pro Val Ser Leu Glu Pro Trp Gly Asp Glu Glu 35 40 45 Arg Leu Arg Val Gln Phe Leu Ala Gln Gln Ser Leu Ser Leu Ala 50 55 60 Pro Val Thr Ala Ala Thr Ala Arg Thr Ala Leu Ser Gly Leu Ser 65 70 75 Gly Ala Asp Gly Arg Arg Glu Glu Arg Gly Arg Gly Lys Ser Trp 80 85 90 Val Cys Leu Ser Leu Gly Gly Ser Gly Asn Thr Glu Pro Gln Lys 95 100 105 Lys Gly Leu Ser Cys Arg Leu Trp Asp Ser Asp Ile Leu Cys Leu 110 115 120 Pro Gly Asp Ile Val Pro Ala Pro Gly Pro Val Leu Ala Pro Thr 125 130 135 His Leu Gln Thr Glu Leu Val Leu Arg Cys Gln Lys Glu Thr Asp 140 145 150 Cys Asp Leu Cys Leu Arg Val Ala Val His Leu Ala Val His Gly 155 160 165 His Trp Glu Glu Pro Glu Asp Glu Glu Lys Phe Gly Gly Ala Ala 170 175 180 Asp Ser Gly Val Glu Glu Pro Arg Asn Ala Ser Leu Gln Ala Gln 185 190 195 Val Val Leu Ser Phe Gln Ala Tyr Pro Thr Ala Arg Cys Val Leu 200 205 210 Leu Glu Val Gln Val Pro Ala Ala Leu Val Gln Phe Gly Gln Ser 215 220 225 Val Gly Ser Val Val Tyr Asp Cys Phe Glu Ala Ala Leu Gly Ser 230 235 240 Glu Val Arg Ile Trp Ser Tyr Thr Gln Pro Arg Tyr Glu Lys Glu 245 250 255 Leu Asn His Thr Gln Gln Leu Pro Ala Leu Pro Trp Leu Asn Val 260 265 270 Ser Ala Asp Gly Asp Asn Val His Leu Val Leu Asn Val Ser Glu 275 280 285 Glu Gln His Phe Gly Leu Ser Leu Tyr Trp Asn Gln Val Gln Gly 290 295 300 Pro Pro Lys Pro Arg Trp His Lys Asn Leu Thr Gly Pro Gln Ile 305 310 315 Ile Thr Leu Asn His Thr Asp Leu Val Pro Cys Leu Cys Ile Gln 320 325 330 Val Trp Pro Leu Glu Pro Asp Ser Val Arg Thr Asn Ile Cys Pro 335 340 345 Phe Arg Glu Asp Pro Arg Ala His Gln Asn Leu Trp Gln Ala Ala 350 355 360 Arg Leu Arg Leu Leu Thr Leu Gln Ser Trp Leu Leu Asp Ala Pro 365 370 375 Cys Ser Leu Pro Ala Glu Ala Ala Leu Cys Trp Arg Ala Pro Gly 380 385 390 Gly Asp Pro Cys Gln Pro Leu Val Pro Pro Leu Ser Trp Glu Asn 395 400 405 Val Thr Val Asp Lys Val Leu Glu Phe Pro Leu Leu Lys Gly His 410 415 420 Pro Asn Leu Cys Val Gln Val Asn Ser Ser Glu Lys Leu Gln Leu 425 430 435 Gln Glu Cys Leu Trp Ala Asp Ser Leu Gly Pro Leu Lys Asp Asp 440 445 450 Val Leu Leu Leu Glu Thr Arg Gly Pro Gln Asp Asn Arg Ser Leu 455 460 465 Cys Ala Leu Glu Pro Ser Gly Cys Thr Ser Leu Pro Ser Lys Ala 470 475 480 Ser Thr Arg Ala Ala Arg Leu Gly Glu Tyr Leu Leu Gln Asp Leu 485 490 495 Gln Ser Gly Gln Cys Leu Gln Leu Trp Asp Asp Asp Leu Gly Ala 500 505 510 Leu Trp Ala Cys Pro Met Asp Lys Tyr Ile His Lys Arg Trp Ala 515 520 525 Leu Val Trp Leu Ala Cys Leu Leu Phe Ala Ala Ala Leu Ser Leu 530 535 540 Ile Leu Leu Leu Lys Lys Asp His Ala Lys Gly Trp Leu Arg Leu 545 550 555 Leu Lys Gln Asp Val Arg Ser Gly Ala Ala Ala Arg Gly Arg Ala 560 565 570 Ala Leu Leu Leu Tyr Ser Ala Asp Asp Ser Gly Phe Glu Arg Leu 575 580 585 Val Gly Ala Leu Ala Ser Ala Leu Cys Gln Leu Pro Leu Arg Val 590 595 600 Ala Val Asp Leu Trp Ser Arg Arg Glu Leu Ser Ala Gln Gly Pro 605 610 615 Val Ala Trp Phe His Ala Gln Arg Arg Gln Thr Leu Gln Glu Gly 620 625 630 Gly Val Val Val Leu Leu Phe Ser Pro Gly Ala Val Ala Leu Cys 635 640 645 Ser Glu Trp Leu Gln Asp Gly Val Ser Gly Pro Gly Ala His Gly 650 655 660 Pro His Asp Ala Phe Arg Ala Ser Leu Ser Cys Val Leu Pro Asp 665 670 675 Phe Leu Gln Gly Arg Ala Pro Gly Ser Tyr Val Gly Ala Cys Phe 680 685 690 Asp Arg Leu Leu His Pro Asp Ala Val Pro Ala Leu Phe Arg Thr 695 700 705 Val Pro Val Phe Thr Leu Pro Ser Gln Leu Pro Asp Phe Leu Gly 710 715 720 Ala Leu Gln Gln Pro Arg Ala Pro Arg Ser Gly Arg Leu Gln Glu 725 730 735 Arg Ala Glu Gln Val Ser Arg Ala Leu Gln Pro Ala Leu Asp Ser 740 745 750 Tyr Phe His Pro Pro Gly Thr Pro Ala Pro Gly Arg Gly Val Gly 755 760 765 Pro Gly Ala Gly Pro Gly Ala Gly Asp Gly Thr 770 775 9 428 PRT Homo sapiens misc_feature Incyte ID No 1633319CD1 9 Met Arg Asn Ala Thr Ser Ala Leu Gly Pro Glu Leu Arg Cys Leu 1 5 10 15 Gly Ala Ala Val His Pro Asp Pro Glu His Ser Gln Ala Lys Val 20 25 30 Ser Leu Ala Cys Val Gly Arg Arg Leu Val Cys Gly Ala Arg Arg 35 40 45 Ala Val Glu Lys Ser Glu Arg Ile Arg Met Glu Ala Val Ala Thr 50 55 60 Ala Thr Ala Ala Lys Glu Pro Asp Lys Gly Cys Ile Glu Pro Gly 65 70 75 Pro Gly His Trp Gly Glu Leu Ser Arg Thr Pro Val Pro Ser Lys 80 85 90 Pro Gln Asp Lys Val Glu Ala Ala Glu Ala Thr Pro Val Ala Leu 95 100 105 Asp Ser Asp Thr Ser Gly Ala Glu Asn Ala Ala Val Ser Ala Met 110 115 120 Leu His Ala Val Ala Ala Ser Arg Leu Pro Val Cys Ser Gln Gln 125 130 135 Gln Gly Glu Pro Asp Leu Thr Glu His Glu Lys Val Ala Ile Leu 140 145 150 Ala Gln Leu Tyr His Glu Lys Pro Leu Val Phe Leu Glu Arg Phe 155 160 165 Arg Thr Gly Leu Arg Glu Glu His Leu Ala Cys Phe Gly His Val 170 175 180 Arg Gly Asp His Arg Ala Asp Phe Tyr Cys Ala Glu Val Ala Arg 185 190 195 Gln Gly Thr Ala Arg Pro Arg Thr Leu Arg Thr Arg Leu Arg Asn 200 205 210 Arg Arg Tyr Ala Ala Leu Arg Glu Leu Ile Gln Gly Gly Glu Tyr 215 220 225 Phe Ser Asp Glu Gln Met Arg Phe Arg Ala Pro Leu Leu Tyr Glu 230 235 240 Gln Tyr Ile Gly Gln Tyr Leu Thr Gln Glu Glu Leu Ser Ala Arg 245 250 255 Thr Pro Thr His Gln Pro Pro Lys Pro Gly Ser Pro Gly Arg Pro 260 265 270 Ala Cys Pro Leu Ser Asn Leu Leu Leu Gln Ser Tyr Glu Glu Arg 275 280 285 Glu Leu Gln Gln Arg Leu Leu Gln Gln Gln Glu Glu Glu Glu Ala 290 295 300 Cys Leu Glu Glu Glu Glu Glu Glu Glu Asp Ser Asp Glu Glu Asp 305 310 315 Gln Arg Ser Gly Lys Asp Ser Glu Ala Trp Val Pro Asp Ser Glu 320 325 330 Glu Arg Leu Ile Leu Arg Glu Glu Phe Thr Ser Arg Met His Gln 335 340 345 Arg Phe Leu Asp Gly Lys Asp Gly Asp Phe Asp Tyr Arg Cys Ser 350 355 360 Cys Ala Ser Thr Ser Pro Ser Pro Ser Pro Ala Ser His Gly Leu 365 370 375 Trp Ser His Ala Glu Pro Leu Thr Ser Cys Gly Gly Leu Pro Leu 380 385 390 Trp Ser Tyr Lys Ala Pro Lys Gln Phe Gln Asp Val Gly Leu Asn 395 400 405 Ser Gln Arg Lys Arg Leu Gly Asp Leu Gly Leu Ala Leu Ser Ile 410 415 420 Ser Asp Pro Gln Ser Pro His Leu 425 10 264 PRT Homo sapiens misc_feature Incyte ID No 1712631CD1 10 Met Leu Arg Cys Gly Gly Arg Gly Leu Leu Leu Gly Leu Ala Val 1 5 10 15 Ala Ala Ala Ala Val Met Ala Ala Arg Leu Met Gly Trp Trp Gly 20 25 30 Pro Arg Ala Gly Phe Arg Leu Phe Ile Pro Glu Glu Leu Ser Arg 35 40 45 Tyr Arg Gly Gly Pro Gly Asp Pro Gly Leu Tyr Leu Ala Leu Leu 50 55 60 Gly Arg Val Tyr Asp Val Ser Ser Gly Arg Arg His Tyr Glu Pro 65 70 75 Gly Ser His Tyr Ser Gly Phe Ala Gly Arg Asp Ala Ser Arg Ala 80 85 90 Phe Val Thr Gly Asp Cys Ser Glu Ala Gly Leu Val Asp Asp Val 95 100 105 Ser Asp Leu Ser Ala Ala Glu Met Leu Thr Leu His Asn Trp Leu 110 115 120 Ser Phe Tyr Glu Lys Asn Tyr Val Cys Val Gly Arg Val Thr Gly 125 130 135 Arg Phe Tyr Gly Glu Asp Gly Leu Pro Thr Pro Ala Leu Thr Gln 140 145 150 Val Glu Ala Ala Ile Thr Arg Gly Leu Glu Ala Asn Lys Leu Gln 155 160 165 Leu Gln Glu Lys Gln Thr Phe Pro Pro Cys Asn Ala Glu Trp Ser 170 175 180 Ser Ala Arg Gly Ser Arg Leu Trp Cys Ser Gln Lys Ser Gly Gly 185 190 195 Val Ser Arg Asp Trp Ile Gly Val Pro Arg Lys Leu Tyr Lys Pro 200 205 210 Gly Ala Lys Glu Pro Arg Cys Val Cys Val Arg Thr Thr Gly Pro 215 220 225 Pro Ser Gly Gln Met Pro Asp Asn Pro Pro His Arg Asn Arg Gly 230 235 240 Asp Leu Asp His Pro Asn Leu Ala Glu Tyr Thr Gly Cys Pro Pro 245 250 255 Leu Ala Ile Thr Cys Ser Phe Pro Leu 260 11 437 PRT Homo sapiens misc_feature Incyte ID No 1795426CD1 11 Met Gly Leu Arg Ala Ala Pro Ser Ser Ala Ala Ala Ala Ala Ala 1 5 10 15 Glu Val Glu Gln Arg Arg Arg Pro Gly Leu Cys Pro Pro Pro Leu 20 25 30 Glu Leu Leu Leu Leu Leu Leu Phe Ser Leu Gly Leu Leu His Ala 35 40 45 Gly Asp Cys Gln Gln Pro Ala Gln Cys Arg Ile Gln Lys Cys Thr 50 55 60 Thr Asp Phe Val Ser Leu Thr Ser His Leu Asn Ser Ala Val Asp 65 70 75 Gly Phe Asp Ser Glu Phe Cys Lys Ala Leu Arg Ala Tyr Ala Gly 80 85 90 Cys Thr Gln Arg Thr Ser Lys Ala Cys Arg Gly Asn Leu Val Tyr 95 100 105 His Ser Ala Val Leu Gly Ile Ser Asp Leu Met Ser Gln Arg Asn 110 115 120 Cys Ser Lys Asp Gly Pro Thr Ser Ser Thr Asn Pro Glu Val Thr 125 130 135 His Asp Pro Cys Asn Tyr His Ser His Ala Gly Ala Arg Glu His 140 145 150 Arg Arg Gly Asp Gln Asn Pro Pro Ser Tyr Leu Phe Cys Gly Leu 155 160 165 Phe Gly Asp Pro His Leu Arg Thr Phe Lys Asp Asn Phe Gln Thr 170 175 180 Cys Lys Val Glu Gly Ala Trp Pro Leu Ile Asp Asn Asn Tyr Leu 185 190 195 Ser Val Gln Val Thr Asn Val Pro Val Val Pro Gly Ser Ser Ala 200 205 210 Thr Ala Thr Asn Lys Ile Thr Ile Ile Phe Lys Ala His His Glu 215 220 225 Cys Thr Asp Gln Lys Val Tyr Gln Ala Val Thr Asp Asp Leu Pro 230 235 240 Ala Ala Phe Val Asp Gly Thr Thr Ser Gly Gly Asp Ser Asp Ala 245 250 255 Lys Ser Leu Arg Ile Val Glu Arg Glu Ser Gly His Tyr Val Glu 260 265 270 Met His Ala Arg Tyr Ile Gly Thr Thr Val Phe Val Arg Gln Val 275 280 285 Gly Arg Tyr Leu Thr Leu Ala Ile Arg Met Pro Glu Asp Leu Ala 290 295 300 Met Ser Tyr Glu Glu Ser Gln Asp Leu Gln Leu Cys Val Asn Gly 305 310 315 Cys Pro Leu Ser Glu Arg Ile Asp Asp Gly Gln Gly Gln Val Ser 320 325 330 Ala Ile Leu Gly His Ser Leu Pro Arg Thr Ser Leu Val Gln Ala 335 340 345 Trp Pro Gly Tyr Thr Leu Glu Thr Ala Asn Thr Gln Cys His Glu 350 355 360 Lys Met Pro Val Lys Asp Ile Tyr Phe Gln Ser Cys Val Phe Asp 365 370 375 Leu Leu Thr Thr Gly Asp Ala Asn Phe Thr Ala Ala Ala His Ser 380 385 390 Ala Leu Glu Asp Val Glu Ala Leu His Pro Arg Lys Glu Arg Trp 395 400 405 His Ile Phe Pro Ser Ser Gly Asn Gly Thr Pro Arg Gly Gly Ser 410 415 420 Asp Leu Ser Val Ser Leu Gly Leu Thr Cys Leu Ile Leu Ile Val 425 430 435 Phe Leu 12 83 PRT Homo sapiens misc_feature Incyte ID No 1329584CD1 12 Met Trp Tyr Phe Met Ser Leu Ile Ser Met Val Leu Leu Leu Ser 1 5 10 15 Pro Ser Cys Ser Asp Leu Leu Val Ile Ser Val Leu Asn Leu Glu 20 25 30 Gln Arg Arg Gln Ser Lys Val Gly Phe Glu Pro Phe Thr Ser Pro 35 40 45 Leu Cys Gly Asp Gly Thr Ile Cys His Leu Thr Gly Tyr His Lys 50 55 60 Thr Glu His Phe Lys Asn Tyr Cys Cys Ala Pro Lys Ile Ile Phe 65 70 75 Ser Lys Cys His Phe Thr Pro Ser 80 13 445 PRT Homo sapiens misc_feature Incyte ID No 3592659CD1 13 Met Leu Leu Phe Val Glu Gln Val Ala Ser Lys Gly Thr Gly Leu 1 5 10 15 Asn Pro Asn Ala Lys Val Trp Gln Glu Ile Ala Pro Gly Asn Thr 20 25 30 Asp Ala Thr Pro Val Thr His Gly Thr Glu Ser Ser Trp His Glu 35 40 45 Ile Ala Ala Thr Ser Gly Ala His Pro Glu Gly Asn Ala Glu Leu 50 55 60 Ser Glu Asp Ile Cys Lys Glu Tyr Glu Val Met Tyr Ser Ser Ser 65 70 75 Cys Glu Thr Thr Arg Asn Thr Thr Gly Ile Glu Glu Ser Thr Asp 80 85 90 Gly Met Ile Leu Gly Pro Glu Asp Leu Ser Tyr Gln Ile Tyr Asp 95 100 105 Val Ser Gly Glu Ser Asn Ser Ala Val Ser Thr Glu Asp Leu Lys 110 115 120 Glu Cys Leu Lys Lys Gln Leu Glu Phe Cys Phe Ser Arg Glu Asn 125 130 135 Leu Ser Lys Asp Leu Tyr Leu Ile Ser Gln Met Asp Ser Asp Gln 140 145 150 Phe Ile Pro Ile Trp Thr Val Ala Asn Met Glu Glu Ile Lys Lys 155 160 165 Leu Thr Thr Asp Pro Asp Leu Ile Leu Glu Val Leu Arg Ser Ser 170 175 180 Pro Met Val Gln Val Asp Glu Lys Gly Glu Lys Val Arg Pro Ser 185 190 195 His Lys Arg Cys Ile Val Ile Leu Arg Glu Ile Pro Glu Thr Thr 200 205 210 Pro Ile Glu Glu Val Lys Gly Leu Phe Lys Ser Glu Asn Cys Pro 215 220 225 Lys Val Ile Ser Cys Glu Phe Ala His Asn Ser Asn Trp Tyr Ile 230 235 240 Thr Phe Gln Ser Asp Thr Asp Ala Gln Gln Ala Phe Lys Tyr Leu 245 250 255 Arg Glu Glu Val Lys Thr Phe Gln Gly Lys Pro Ile Met Ala Arg 260 265 270 Ile Lys Ala Ile Asn Thr Phe Phe Ala Lys Asn Gly Tyr Arg Leu 275 280 285 Met Asp Ser Ser Ile Tyr Ser His Pro Ile Gln Thr Gln Ala Gln 290 295 300 Tyr Ala Ser Pro Val Phe Met Gln Pro Val Tyr Asn Pro His Gln 305 310 315 Gln Tyr Ser Val Tyr Ser Ile Val Pro Gln Ser Trp Ser Pro Asn 320 325 330 Pro Thr Pro Tyr Phe Glu Thr Pro Leu Ala Pro Phe Pro Asn Gly 335 340 345 Ser Phe Val Asn Gly Phe Asn Ser Pro Gly Ser Tyr Lys Thr Asn 350 355 360 Ala Ala Ala Met Asn Met Gly Arg Pro Phe Gln Lys Asn Arg Val 365 370 375 Lys Pro Gln Phe Arg Ser Ser Gly Gly Ser Glu His Ser Thr Glu 380 385 390 Gly Ser Val Ser Leu Gly Asp Gly Gln Leu Asn Arg Tyr Ser Ser 395 400 405 Arg Asn Phe Pro Ala Glu Arg His Asn Pro Thr Val Thr Gly His 410 415 420 Gln Glu Gln Thr Tyr Leu Gln Lys Glu Thr Ser Thr Leu Gln Val 425 430 435 Glu Gln Asn Gly Asp Tyr Gly Arg Gly Arg 440 445 14 563 PRT Homo sapiens misc_feature Incyte ID No 7596081CD1 14 Met Glu Pro Leu Arg Ala Pro Ala Leu Arg Arg Leu Leu Pro Pro 1 5 10 15 Leu Leu Leu Leu Leu Leu Ser Leu Pro Pro Arg Ala Arg Ala Lys 20 25 30 Tyr Val Arg Gly Asn Leu Ser Ser Lys Glu Asp Trp Val Phe Leu 35 40 45 Thr Arg Phe Cys Phe Leu Ser Asp Tyr Gly Arg Leu Asp Phe Arg 50 55 60 Phe Arg Tyr Pro Glu Ala Lys Cys Cys Gln Asn Ile Leu Leu Tyr 65 70 75 Phe Asp Asp Pro Ser Gln Trp Pro Ala Val Tyr Lys Ala Gly Asp 80 85 90 Lys Asp Cys Leu Ala Lys Glu Ser Val Ile Arg Pro Glu Asn Asn 95 100 105 Gln Val Ile Asn Leu Thr Thr Gln Tyr Ala Trp Ser Gly Cys Gln 110 115 120 Val Val Ser Glu Glu Gly Thr Arg Tyr Leu Ser Cys Ser Ser Gly 125 130 135 Arg Ser Phe Arg Ser Val Arg Glu Arg Trp Trp Tyr Ile Ala Leu 140 145 150 Ser Lys Cys Gly Gly Asp Gly Leu Gln Leu Glu Tyr Glu Met Val 155 160 165 Leu Thr Asn Gly Lys Ser Phe Trp Thr Arg His Phe Ser Ala Asp 170 175 180 Glu Phe Gly Ile Leu Glu Thr Asp Val Thr Phe Leu Leu Ile Phe 185 190 195 Ile Leu Ile Phe Phe Leu Ser Cys Tyr Phe Gly Tyr Leu Leu Lys 200 205 210 Gly Arg Gln Leu Leu His Thr Thr Tyr Lys Met Phe Met Ala Ala 215 220 225 Ala Gly Val Glu Val Leu Ser Leu Leu Phe Phe Cys Ile Tyr Trp 230 235 240 Gly Gln Tyr Ala Thr Asp Gly Ile Gly Asn Glu Ser Val Lys Ile 245 250 255 Leu Ala Lys Leu Leu Phe Ser Ser Ser Phe Leu Ile Phe Leu Leu 260 265 270 Met Leu Ile Leu Leu Gly Lys Gly Phe Thr Val Thr Arg Gly Arg 275 280 285 Ile Ser His Ala Gly Ser Val Lys Leu Ser Val Tyr Met Thr Leu 290 295 300 Tyr Thr Leu Thr His Val Val Leu Leu Ile Tyr Glu Ala Glu Phe 305 310 315 Phe Asp Pro Gly Gln Val Leu Tyr Thr Tyr Glu Ser Pro Ala Gly 320 325 330 Tyr Gly Leu Ile Gly Leu Gln Val Ala Ala Tyr Val Trp Phe Cys 335 340 345 Tyr Ala Val Leu Val Ser Leu Arg His Phe Pro Glu Lys Gln Pro 350 355 360 Phe Tyr Val Pro Phe Phe Ala Ala Tyr Thr Leu Trp Phe Phe Ala 365 370 375 Val Pro Val Met Ala Leu Ile Ala Asn Phe Gly Ile Pro Lys Trp 380 385 390 Ala Arg Glu Lys Ile Val Asn Gly Ile Gln Leu Gly Ile His Leu 395 400 405 Tyr Ala His Gly Val Phe Leu Ile Met Thr Arg Pro Ser Ala Ala 410 415 420 Asn Lys Asn Phe Pro Tyr His Val Arg Thr Ser Gln Ile Ala Ser 425 430 435 Ala Gly Val Pro Gly Pro Gly Gly Ser Gln Ser Ala Asp Lys Ala 440 445 450 Phe Pro Gln His Val Tyr Gly Asn Val Thr Phe Ile Ser Asp Ser 455 460 465 Val Pro Asn Phe Thr Glu Leu Phe Ser Ile Pro Pro Pro Ala Thr 470 475 480 Ser Ala Gly Lys Gln Val Glu Glu Thr Ala Val Ala Ala Ala Val 485 490 495 Ala Pro Arg Gly Arg Val Val Thr Met Ala Glu Pro Gly Ala Ala 500 505 510 Ser Pro Pro Leu Pro Ala Arg Phe Pro Lys Ala Ala Asp Ser Gly 515 520 525 Trp Asp Gly Pro Thr Pro Pro Tyr Gln Pro Leu Val Pro Gln Thr 530 535 540 Ala Ala Pro His Thr Gly Phe Thr Glu Tyr Phe Ser Met His Thr 545 550 555 Ala Gly Gly Thr Ala Pro Pro Val 560 15 410 PRT Homo sapiens misc_feature Incyte ID No 3009869CD1 15 Met Leu Ser Leu Leu Gln Thr Ser Thr Ser Ser Ser Val Gly Leu 1 5 10 15 Pro Pro Val Pro Pro Ser Ser Ser Leu Ser Ser Leu Lys Ser Lys 20 25 30 Gln Asp Gly Asp Leu Arg Gly Pro Glu Asn Pro Arg Asn Ile His 35 40 45 Thr Tyr Pro Ser Thr Leu Ala Ser Ser Ala Leu Ser Ser Leu Ser 50 55 60 Pro Pro Ile Asn Gln Arg Ala Thr Phe Ser Ser Ser Glu Lys Cys 65 70 75 Phe His Pro Ser Pro Ala Leu Ser Ser Leu Ile Asn Arg Ser Lys 80 85 90 Arg Ala Ser Ser Gln Leu Ser Gly Gln Glu Leu Asn Pro Ser Ala 95 100 105 Leu Pro Ser Leu Pro Val Ser Ser Ala Asp Phe Ala Ser Leu Pro 110 115 120 Asn Leu Arg Ser Ser Ser Leu Pro His Ala Asn Leu Pro Thr Leu 125 130 135 Val Pro Gln Leu Ser Pro Ser Ala Leu His Pro His Cys Gly Ser 140 145 150 Gly Thr Leu Pro Ser Arg Leu Gly Lys Ser Glu Ser Thr Thr Pro 155 160 165 Asn His Arg Ser Pro Val Ser Thr Pro Ser Leu Pro Ile Ser Leu 170 175 180 Thr Arg Thr Glu Glu Leu Ile Ser Pro Cys Ala Leu Ser Met Ser 185 190 195 Thr Gly Pro Glu Asn Lys Lys Ser Lys Gln Tyr Lys Thr Lys Ser 200 205 210 Ser Tyr Lys Ala Phe Ala Ala Ile Pro Thr Asn Thr Leu Leu Leu 215 220 225 Glu Gln Lys Ala Leu Asp Glu Pro Ala Lys Thr Glu Ser Val Ser 230 235 240 Lys Asp Asn Thr Leu Glu Pro Pro Val Glu Thr Pro Thr Thr Leu 245 250 255 Pro Arg Ala Ala Gly Arg Glu Thr Lys Tyr Ala Asn Leu Ser Ser 260 265 270 Pro Thr Ser Thr Val Ser Glu Ser Gln Leu Thr Lys Pro Gly Val 275 280 285 Ile Arg Pro Val Pro Val Lys Ser Arg Ile Leu Leu Lys Lys Glu 290 295 300 Glu Glu Val Tyr Glu Pro Asn Pro Phe Ser Lys Tyr Leu Glu Asp 305 310 315 Asn Ser Asp Leu Phe Ser Glu Gln Asp Val Thr Val Pro Pro Lys 320 325 330 Pro Val Ser Leu His Pro Leu Tyr Gln Thr Lys Leu Tyr Pro Pro 335 340 345 Ala Lys Ser Leu Leu His Pro Gln Thr Leu Ser His Ala Asp Cys 350 355 360 Leu Ala Pro Gly Pro Phe Ser His Leu Ser Phe Ser Leu Ser Asp 365 370 375 Glu Gln Glu Asn Ser His Thr Leu Leu Ser His Asn Ala Cys Asn 380 385 390 Lys Leu Ser His Pro Met Val Ala Ile Pro Glu His Glu Ala Leu 395 400 405 Asp Ser Lys Glu Gln 410 16 1461 PRT Homo sapiens misc_feature Incyte ID No 7349094CD1 16 Met Ala Ala Gly Gly Gly Gly Gly Ser Ser Lys Ala Ser Ser Ser 1 5 10 15 Ser Ala Ser Ser Ala Gly Ala Leu Glu Ser Ser Leu Asp Arg Lys 20 25 30 Phe Gln Ser Val Thr Asn Thr Met Glu Ser Ile Gln Gly Leu Ser 35 40 45 Ser Trp Cys Ile Glu Asn Lys Lys His His Ser Thr Ile Val Tyr 50 55 60 His Trp Met Lys Trp Leu Arg Arg Ser Ala Tyr Pro His Arg Leu 65 70 75 Asn Leu Phe Tyr Leu Ala Asn Asp Val Ile Gln Asn Cys Lys Arg 80 85 90 Lys Asn Ala Ile Ile Phe Arg Glu Ser Phe Ala Asp Val Leu Pro 95 100 105 Glu Ala Ala Ala Leu Val Lys Asp Pro Ser Val Ser Lys Ser Val 110 115 120 Glu Arg Ile Phe Lys Ile Trp Glu Asp Arg Asn Val Tyr Pro Glu 125 130 135 Glu Met Ile Val Ala Leu Arg Glu Ala Leu Ser Thr Thr Phe Lys 140 145 150 Thr Gln Lys Gln Leu Lys Glu Asn Leu Asn Lys Gln Pro Asn Lys 155 160 165 Gln Trp Lys Lys Ser Gln Thr Ser Thr Asn Pro Lys Ala Ala Leu 170 175 180 Lys Ser Lys Ile Val Ala Glu Phe Arg Ser Gln Ala Leu Ile Glu 185 190 195 Glu Leu Leu Leu Tyr Lys Arg Ser Glu Asp Gln Ile Glu Leu Lys 200 205 210 Glu Lys Gln Leu Ser Thr Met Arg Val Asp Val Cys Ser Thr Glu 215 220 225 Thr Leu Lys Cys Leu Lys Asp Lys Thr Gly Gly Lys Lys Phe Ser 230 235 240 Lys Glu Phe Glu Glu Ala Ser Ser Lys Leu Glu Glu Phe Val Asn 245 250 255 Gly Leu Asp Lys Gln Val Lys Asn Gly Pro Ser Leu Thr Glu Ala 260 265 270 Leu Glu Asn Ala Gly Ile Phe Tyr Glu Ala Gln Tyr Lys Glu Val 275 280 285 Lys Val Val Ala Asn Ala Tyr Lys Thr Phe Ala Asn Arg Val Asn 290 295 300 Asn Leu Lys Lys Lys Leu Asp Gln Leu Lys Ser Thr Leu Pro Asp 305 310 315 Pro Glu Glu Ser Pro Val Pro Ser Pro Ser Met Asp Ala Pro Ser 320 325 330 Pro Thr Gly Ser Glu Ser Pro Phe Gln Gly Met Gly Gly Glu Glu 335 340 345 Ser Gln Ser Pro Thr Met Glu Ser Glu Lys Ser Ala Thr Pro Glu 350 355 360 Pro Val Thr Asp Asn Arg Asp Val Glu Asp Met Glu Leu Ser Asp 365 370 375 Val Glu Asp Asp Gly Ser Lys Ile Ile Val Glu Asp Arg Lys Glu 380 385 390 Lys Pro Ala Glu Lys Ser Ala Val Ser Thr Ser Val Pro Thr Lys 395 400 405 Pro Thr Glu Asn Ile Ser Lys Ala Ser Ser Cys Thr Pro Val Pro 410 415 420 Val Thr Met Thr Ala Thr Pro Pro Leu Pro Lys Pro Val Asn Thr 425 430 435 Ser Leu Ser Pro Ser Pro Ala Leu Ala Leu Pro Asn Leu Ala Asn 440 445 450 Val Asp Leu Ala Lys Ile Ser Ser Ile Leu Ser Ser Leu Thr Ser 455 460 465 Val Met Lys Asn Thr Gly Val Ser Pro Ala Ser Arg Pro Ser Pro 470 475 480 Gly Thr Pro Thr Ser Pro Ser Asn Leu Thr Ser Gly Leu Lys Thr 485 490 495 Pro Ala Pro Ala Thr Thr Thr Ser His Asn Pro Leu Ala Asn Ile 500 505 510 Leu Ser Lys Val Glu Ile Thr Pro Glu Ser Ile Leu Ser Ala Leu 515 520 525 Ser Lys Thr Gln Thr Gln Ser Ala Pro Ala Leu Gln Gly Leu Ser 530 535 540 Ser Leu Leu Gln Ser Val Thr Gly Asn Pro Val Pro Ala Ser Glu 545 550 555 Ala Ala Ser Gln Ser Thr Ser Ala Ser Pro Ala Asn Thr Thr Val 560 565 570 Ser Thr Ile Lys Gly Arg Asn Leu Pro Ser Ser Ala Gln Pro Phe 575 580 585 Ile Pro Lys Ser Phe Asn Tyr Ser Pro Asn Ser Ser Thr Ser Glu 590 595 600 Val Ser Ser Thr Ser Ala Ser Lys Ala Ser Ile Gly Gln Ser Pro 605 610 615 Gly Leu Pro Ser Thr Thr Phe Lys Leu Pro Ser Asn Ser Leu Gly 620 625 630 Phe Thr Ala Thr His Asn Thr Ser Pro Ala Ala Pro Pro Thr Glu 635 640 645 Val Thr Ile Cys Gln Ser Ser Glu Val Ser Lys Pro Lys Leu Glu 650 655 660 Ser Glu Ser Thr Ser Pro Ser Leu Glu Met Lys Ile His Asn Phe 665 670 675 Leu Lys Gly Asn Pro Gly Phe Ser Gly Leu Asn Leu Asn Ile Pro 680 685 690 Ile Leu Ser Ser Leu Gly Ser Ser Ala Pro Ser Glu Ser His Pro 695 700 705 Ser Asp Phe Gln Arg Gly Pro Thr Ser Thr Ser Ile Asp Asn Ile 710 715 720 Asp Gly Thr Pro Val Arg Asp Glu Arg Ser Gly Thr Pro Thr Gln 725 730 735 Asp Glu Met Met Asp Lys Pro Thr Ser Ser Ser Val Asp Thr Met 740 745 750 Ser Leu Leu Ser Lys Ile Ile Ser Pro Gly Ser Ser Thr Pro Ser 755 760 765 Ser Thr Arg Ser Pro Pro Pro Gly Arg Asp Glu Ser Tyr Pro Arg 770 775 780 Glu Leu Ser Asn Ser Val Ser Thr Tyr Arg Pro Phe Gly Leu Gly 785 790 795 Ser Glu Ser Pro Tyr Lys Gln Pro Ser Asp Gly Met Glu Arg Pro 800 805 810 Ser Ser Leu Met Asp Ser Ser Gln Glu Lys Phe Tyr Pro Asp Thr 815 820 825 Ser Phe Gln Glu Asp Glu Asp Tyr Arg Asp Phe Glu Tyr Ser Gly 830 835 840 Pro Pro Pro Ser Ala Met Met Asn Leu Glu Lys Lys Pro Ala Lys 845 850 855 Ser Ile Leu Lys Ser Ser Lys Leu Ser Asp Thr Thr Glu Tyr Gln 860 865 870 Pro Ile Leu Ser Ser Tyr Ser His Arg Ala Gln Glu Phe Gly Val 875 880 885 Lys Ser Ala Phe Pro Pro Ser Val Arg Ala Leu Leu Asp Ser Ser 890 895 900 Glu Asn Cys Asp Arg Leu Ser Ser Ser Pro Gly Leu Phe Gly Ala 905 910 915 Phe Ser Val Arg Gly Asn Glu Pro Gly Ser Asp Arg Ser Pro Ser 920 925 930 Pro Ser Lys Asn Asp Ser Phe Phe Thr Pro Asp Ser Asn His Asn 935 940 945 Ser Leu Ser Gln Ser Thr Thr Gly His Leu Ser Leu Pro Gln Lys 950 955 960 Gln Tyr Pro Asp Ser Pro His Pro Val Pro His Arg Ser Leu Phe 965 970 975 Ser Pro Gln Asn Thr Leu Ala Ala Pro Thr Gly His Pro Pro Thr 980 985 990 Ser Gly Val Glu Lys Val Leu Ala Ser Thr Ile Ser Thr Thr Ser 995 1000 1005 Thr Ile Glu Phe Lys Asn Met Leu Lys Asn Ala Ser Arg Lys Pro 1010 1015 1020 Ser Asp Asp Lys His Phe Gly Gln Ala Pro Ser Lys Gly Thr Pro 1025 1030 1035 Ser Asp Gly Val Ser Leu Ser Asn Leu Thr Gln Pro Ser Leu Thr 1040 1045 1050 Ala Thr Asp Gln Gln Gln Gln Glu Glu His Tyr Arg Ile Glu Thr 1055 1060 1065 Arg Val Ser Ser Ser Cys Leu Asp Leu Pro Asp Ser Thr Glu Glu 1070 1075 1080 Lys Gly Ala Pro Ile Glu Thr Leu Gly Tyr His Ser Ala Ser Asn 1085 1090 1095 Arg Arg Met Ser Gly Glu Pro Ile Gln Thr Val Glu Ser Ile Arg 1100 1105 1110 Val Pro Gly Lys Gly Asn Arg Gly His Gly Arg Glu Ala Ser Arg 1115 1120 1125 Val Gly Trp Phe Asp Leu Ser Thr Ser Gly Ser Ser Phe Asp Asn 1130 1135 1140 Gly Pro Ser Ser Ala Ser Glu Leu Ala Ser Leu Gly Gly Gly Gly 1145 1150 1155 Ser Gly Gly Leu Thr Gly Phe Lys Thr Ala Pro Tyr Lys Glu Arg 1160 1165 1170 Ala Pro Gln Phe Gln Glu Ser Val Gly Ser Phe Arg Ser Asn Ser 1175 1180 1185 Phe Asn Ser Thr Phe Glu His His Leu Pro Pro Ser Pro Leu Glu 1190 1195 1200 His Gly Thr Pro Phe Gln Arg Glu Pro Val Gly Pro Ser Ser Ala 1205 1210 1215 Pro Pro Val Pro Pro Lys Asp His Gly Gly Ile Phe Ser Arg Asp 1220 1225 1230 Ala Pro Thr His Leu Pro Ser Val Asp Leu Ser Asn Pro Phe Thr 1235 1240 1245 Lys Glu Ala Ala Leu Ala His Ala Ala Pro Pro Pro Pro Pro Gly 1250 1255 1260 Glu His Ser Gly Ile Pro Phe Pro Thr Pro Pro Pro Pro Pro Pro 1265 1270 1275 Pro Gly Glu His Ser Ser Ser Gly Gly Ser Gly Val Pro Phe Ser 1280 1285 1290 Thr Pro Pro Pro Pro Pro Pro Pro Val Asp His Ser Gly Val Val 1295 1300 1305 Pro Phe Pro Ala Pro Pro Leu Ala Glu His Gly Val Ala Gly Ala 1310 1315 1320 Val Ala Val Phe Pro Lys Asp His Ser Ser Leu Leu Gln Gly Thr 1325 1330 1335 Leu Ala Glu His Phe Gly Val Leu Pro Gly Pro Arg Asp His Gly 1340 1345 1350 Gly Pro Thr Gln Arg Asp Leu Asn Gly Pro Gly Leu Ser Arg Val 1355 1360 1365 Arg Glu Ser Leu Thr Leu Pro Ser His Ser Leu Glu His Leu Gly 1370 1375 1380 Pro Pro His Gly Gly Gly Gly Gly Gly Gly Ser Asn Ser Ser Ser 1385 1390 1395 Gly Pro Pro Leu Gly Pro Ser His Arg Asp Thr Ile Ser Arg Ser 1400 1405 1410 Gly Ile Ile Leu Arg Ser Pro Arg Pro Asp Phe Arg Pro Arg Glu 1415 1420 1425 Pro Phe Leu Ser Arg Asp Pro Phe His Ser Leu Lys Arg Pro Arg 1430 1435 1440 Pro Pro Phe Ala Arg Gly Pro Pro Phe Phe Ala Pro Lys Arg Pro 1445 1450 1455 Phe Phe Pro Pro Arg Tyr 1460 17 402 PRT Homo sapiens misc_feature Incyte ID No 6826956CD1 17 Met Val Cys Ala Arg Ala Ala Leu Gly Pro Gly Ala Leu Trp Ala 1 5 10 15 Ala Ala Trp Gly Val Leu Leu Leu Thr Ala Pro Ala Gly Ala Gln 20 25 30 Arg Gly Arg Lys Lys Val Val His Val Leu Glu Gly Glu Ser Gly 35 40 45 Ser Val Val Val Gln Thr Ala Pro Gly Gln Val Val Ser His Arg 50 55 60 Gly Gly Thr Ile Val Leu Pro Cys Arg Tyr His Tyr Glu Ala Ala 65 70 75 Ala His Gly His Asp Gly Val Arg Leu Lys Trp Thr Lys Val Val 80 85 90 Asp Pro Leu Ala Phe Thr Asp Val Phe Val Ala Leu Gly Pro Gln 95 100 105 His Arg Ala Phe Gly Ser Tyr Arg Gly Arg Ala Glu Leu Gln Gly 110 115 120 Asp Gly Pro Gly Asp Ala Ser Leu Val Leu Arg Asn Val Thr Leu 125 130 135 Gln Asp Tyr Gly Arg Tyr Glu Cys Glu Val Thr Asn Glu Leu Glu 140 145 150 Asp Asp Ala Gly Met Val Lys Leu Asp Leu Glu Gly Val Val Phe 155 160 165 Pro Tyr His Pro Arg Gly Gly Arg Tyr Lys Leu Thr Phe Ala Glu 170 175 180 Ala Gln Arg Ala Cys Ala Glu Gln Asp Gly Ile Leu Ala Ser Ala 185 190 195 Glu Gln Leu His Ala Ala Trp Arg Asp Gly Leu Asp Trp Cys Asn 200 205 210 Ala Gly Trp Leu Arg Asp Gly Ser Val Gln Tyr Pro Val Asn Arg 215 220 225 Pro Arg Glu Pro Cys Gly Gly Leu Gly Gly Thr Gly Ser Ala Gly 230 235 240 Gly Gly Gly Asp Ala Asn Gly Gly Leu Arg Asn Tyr Gly Tyr Arg 245 250 255 His Asn Ala Glu Glu Arg Tyr Asp Ala Phe Cys Phe Thr Ser Asn 260 265 270 Leu Pro Gly Arg Val Phe Phe Leu Lys Pro Leu Arg Pro Val Pro 275 280 285 Phe Ser Gly Ala Ala Arg Ala Cys Ala Ala Arg Gly Ala Ala Val 290 295 300 Ala Lys Val Gly Gln Leu Phe Ala Ala Trp Lys Leu Gln Leu Leu 305 310 315 Asp Arg Cys Thr Gly Gly Trp Leu Ala Asp Gly Ser Ala Arg Tyr 320 325 330 Pro Ile Val Asn Pro Arg Ala Arg Cys Gly Gly Arg Arg Pro Gly 335 340 345 Val Arg Ser Leu Gly Phe Pro Asp Ala Thr Arg Arg Leu Phe Gly 350 355 360 Val Tyr Cys Tyr Arg Ala Pro Gly Ala Pro Asp Pro Ala Pro Gly 365 370 375 Gly Trp Gly Trp Gly Trp Ala Gly Gly Gly Gly Trp Ala Gly Gly 380 385 390 Ala Arg Asp Pro Ala Ala Trp Thr Pro Leu His Val 395 400 18 450 PRT Homo sapiens misc_feature Incyte ID No 7486351CD1 18 Met Asp Leu Ser Ala Ala Ala Ala Leu Cys Leu Trp Leu Leu Ser 1 5 10 15 Ala Cys Arg Pro Arg Asp Gly Leu Glu Ala Ala Ala Val Leu Arg 20 25 30 Ala Ala Gly Ala Gly Pro Val Arg Ser Pro Gly Gly Gly Gly Gly 35 40 45 Gly Gly Gly Gly Gly Arg Thr Leu Ala Gln Ala Ala Gly Ala Ala 50 55 60 Ala Val Pro Ala Ala Ala Val Pro Arg Ala Arg Ala Ala Arg Arg 65 70 75 Ala Ala Gly Ser Gly Phe Arg Asn Gly Ser Val Val Pro His His 80 85 90 Phe Met Met Ser Leu Tyr Arg Ser Leu Ala Gly Arg Ala Pro Ala 95 100 105 Gly Ala Ala Ala Val Ser Ala Ser Gly His Gly Arg Ala Asp Thr 110 115 120 Ile Thr Gly Phe Thr Asp Gln Ala Thr Gln Asp Glu Ser Ala Ala 125 130 135 Glu Thr Gly Gln Ser Phe Leu Phe Asp Val Ser Ser Leu Asn Asp 140 145 150 Ala Asp Glu Val Val Gly Ala Glu Leu Arg Val Leu Arg Arg Gly 155 160 165 Ser Pro Glu Ser Gly Pro Gly Ser Trp Thr Ser Pro Pro Leu Leu 170 175 180 Leu Leu Ser Thr Cys Pro Gly Ala Ala Arg Ala Pro Arg Leu Leu 185 190 195 Tyr Ser Arg Ala Ala Glu Pro Leu Val Gly Gln Arg Trp Glu Ala 200 205 210 Phe Asp Val Ala Asp Ala Met Arg Arg His Arg Arg Glu Pro Arg 215 220 225 Pro Pro Arg Ala Phe Cys Leu Leu Leu Arg Ala Val Ala Gly Pro 230 235 240 Val Pro Ser Pro Leu Ala Leu Arg Arg Leu Gly Phe Gly Trp Pro 245 250 255 Gly Gly Gly Gly Ser Ala Ala Glu Glu Arg Ala Val Leu Val Val 260 265 270 Ser Ser Arg Thr Gln Arg Lys Glu Ser Leu Phe Arg Glu Ile Arg 275 280 285 Ala Gln Ala Arg Ala Leu Gly Ala Ala Leu Ala Ser Glu Pro Leu 290 295 300 Pro Asp Pro Gly Thr Gly Thr Ala Ser Pro Arg Ala Val Ile Gly 305 310 315 Gly Arg Arg Arg Arg Arg Thr Ala Leu Ala Gly Thr Arg Thr Ala 320 325 330 Gln Gly Ser Gly Gly Gly Ala Gly Arg Gly His Gly Arg Arg Gly 335 340 345 Arg Ser Arg Cys Ser Arg Lys Pro Leu His Val Asp Phe Lys Glu 350 355 360 Leu Gly Trp Asp Asp Trp Ile Ile Ala Pro Leu Asp Tyr Glu Ala 365 370 375 Tyr His Cys Glu Gly Leu Cys Asp Phe Pro Leu Arg Ser His Leu 380 385 390 Glu Pro Thr Asn His Ala Ile Ile Gln Thr Leu Leu Asn Ser Met 395 400 405 Ala Pro Asp Ala Ala Pro Ala Ser Cys Cys Val Pro Ala Arg Leu 410 415 420 Ser Pro Ile Ser Ile Leu Tyr Ile Asp Ala Ala Asn Asn Val Val 425 430 435 Tyr Lys Gln Tyr Glu Asp Met Val Val Glu Ala Cys Gly Cys Arg 440 445 450 19 203 PRT Homo sapiens misc_feature Incyte ID No 1709023CD1 19 Met Ser Ala Trp Cys Val Glu Leu Trp Ala His Thr Phe Leu Phe 1 5 10 15 Leu Ser Gln Ile Leu Val Tyr Ser Leu Glu Ala Gly Arg Arg Leu 20 25 30 Leu Lys Leu Gly Asn Val Leu Arg Asp Phe Thr Cys Val Asn Leu 35 40 45 Ser Asp Ser Pro Pro Asn Leu Met Val Ser Gly Asn Met Asp Gly 50 55 60 Arg Val Arg Ile His Asp Leu Arg Ser Gly Asn Ile Ala Leu Ser 65 70 75 Leu Ser Ala His Gln Leu Arg Val Ser Ala Val Gln Met Asp Asp 80 85 90 Trp Lys Ile Val Ser Gly Gly Glu Glu Gly Leu Val Ser Val Trp 95 100 105 Asp Tyr Arg Met Asn Gln Lys Leu Trp Glu Val Tyr Ser Gly His 110 115 120 Pro Val Gln His Ile Ser Phe Ser Ser His Ser Leu Ile Thr Ala 125 130 135 Asn Val Pro Tyr Gln Thr Val Met Arg Asn Ala Asp Leu Asp Ser 140 145 150 Phe Thr Thr His Arg Arg His Arg Gly Leu Ile Arg Ala Tyr Glu 155 160 165 Phe Ala Val Asp Gln Leu Ala Phe Gln Ser Pro Leu Pro Val Cys 170 175 180 Arg Ser Ser Cys Asp Ala Met Ala Thr His Tyr Tyr Asp Leu Ala 185 190 195 Leu Ala Phe Pro Tyr Asn His Val 200 20 133 PRT Homo sapiens misc_feature Incyte ID No 1556012CD1 20 Met Ala Leu Gly Val Pro Ile Ser Val Tyr Leu Leu Phe Asn Ala 1 5 10 15 Met Thr Ala Leu Thr Glu Glu Ala Ala Val Thr Val Thr Pro Pro 20 25 30 Ile Thr Ala Gln Gln Ala Asp Asn Ile Glu Gly Pro Ile Ala Leu 35 40 45 Lys Phe Ser His Leu Cys Leu Glu Asp His Asn Ser Tyr Cys Ile 50 55 60 Asn Gly Ala Cys Ala Phe His His Glu Leu Glu Lys Ala Ile Cys 65 70 75 Arg Cys Phe Thr Gly Tyr Thr Gly Glu Arg Cys Glu His Leu Thr 80 85 90 Leu Thr Ser Tyr Ala Val Asp Ser Tyr Glu Lys Tyr Ile Ala Ile 95 100 105 Gly Ile Gly Val Gly Leu Leu Leu Ser Gly Phe Leu Val Ile Phe 110 115 120 Tyr Cys Tyr Ile Arg Lys Arg Tyr Glu Lys Asp Lys Ile 125 130 21 174 PRT Homo sapiens misc_feature Incyte ID No 1838010CD1 21 Met Thr Ala Glu Phe Leu Ser Leu Leu Cys Leu Gly Leu Cys Leu 1 5 10 15 Gly Tyr Glu Asp Glu Lys Lys Asn Glu Lys Pro Pro Lys Pro Ser 20 25 30 Leu His Ala Trp Pro Ser Ser Val Val Glu Ala Glu Ser Asn Val 35 40 45 Thr Leu Lys Cys Gln Ala His Ser Gln Asn Val Thr Phe Val Leu 50 55 60 Arg Lys Val Asn Asp Ser Gly Tyr Lys Gln Glu Gln Ser Ser Ala 65 70 75 Glu Asn Glu Ala Glu Phe Pro Phe Thr Asp Leu Lys Pro Lys Asp 80 85 90 Ala Gly Arg Tyr Phe Cys Ala Tyr Lys Thr Thr Ala Ser His Glu 95 100 105 Trp Ser Glu Ser Ser Glu His Leu Gln Leu Val Val Thr Asp Lys 110 115 120 His Asp Glu Leu Glu Ala Pro Ser Met Lys Thr Asp Thr Arg Thr 125 130 135 Ile Phe Val Ala Ile Phe Ser Cys Ile Ser Ile Leu Leu Leu Phe 140 145 150 Leu Ser Val Phe Ile Ile Tyr Arg Cys Ser Gln His Ser Glu Leu 155 160 165 Arg Glu Arg Lys Gly Arg Glu Gly Glu 170 22 75 PRT Homo sapiens misc_feature Incyte ID No 1741076CD1 22 Met Lys Leu Phe Pro Glu Phe Cys Pro Phe Ile Ala Leu Ala Cys 1 5 10 15 Cys Pro Leu Ser Thr Ser His Pro Ser Arg Gly Val Ile Arg Ile 20 25 30 Gly Val Gly Thr Glu Pro Arg Cys Leu Met Gly Ser Glu Ala Ser 35 40 45 Pro Pro Gly Glu Ile Ala Cys Arg Phe His Val Cys Val Cys Pro 50 55 60 Leu Asp Pro Cys Ser Arg Pro Arg Cys Pro His Leu Ser Phe Pro 65 70 75 23 575 PRT Homo sapiens misc_feature Incyte ID No 2692031CD1 23 Met Ala Ser Trp Leu Arg Arg Lys Leu Arg Gly Lys Arg Arg Pro 1 5 10 15 Val Ile Ala Phe Cys Leu Leu Met Ile Leu Ser Ala Met Ala Val 20 25 30 Thr Arg Phe Pro Pro Gln Arg Pro Ser Ala Gly Pro Asp Pro Gly 35 40 45 Pro Met Glu Pro Gln Gly Val Thr Gly Ala Pro Ala Thr His Ile 50 55 60 Arg Gln Ala Leu Ser Ser Ser Arg Arg Gln Arg Ala Arg Asn Met 65 70 75 Gly Phe Trp Arg Ser Arg Ala Leu Pro Arg Asn Ser Ile Leu Val 80 85 90 Cys Ala Glu Glu Gln Gly His Arg Ala Arg Val Asp Arg Ser Arg 95 100 105 Glu Ser Pro Gly Gly Asp Leu Arg His Pro Gly Arg Val Arg Arg 110 115 120 Asp Ile Thr Leu Ser Gly His Pro Arg Leu Ser Thr Gln His Val 125 130 135 Val Leu Leu Arg Glu Asp Glu Val Gly Asp Pro Gly Thr Lys Asp 140 145 150 Leu Gly His Pro Gln His Gly Ser Pro Ile Gln Glu Thr Gln Ser 155 160 165 Glu Val Val Thr Leu Val Ser Pro Leu Pro Gly Ser Asp Met Ala 170 175 180 Ala Leu Pro Ala Trp Arg Ala Thr Ser Gly Leu Thr Leu Trp Pro 185 190 195 His Thr Ala Glu Gly Arg Asp Leu Leu Gly Ala Glu Asn Arg Ala 200 205 210 Leu Thr Gly Gly Gln Gln Ala Glu Asp Pro Thr Leu Ala Ser Gly 215 220 225 Ala His Gln Trp Pro Gly Ser Val Glu Lys Leu Gln Gly Ser Val 230 235 240 Trp Cys Asp Ala Glu Thr Leu Leu Ser Ser Ser Arg Thr Gly Gly 245 250 255 Gln Ala Pro Pro Trp Leu Thr Asp His Asp Val Gln Met Leu Arg 260 265 270 Leu Leu Ala Gln Gly Glu Val Val Asp Lys Ala Arg Val Pro Ala 275 280 285 His Gly Gln Val Leu Gln Val Gly Phe Ser Thr Glu Ala Ala Leu 290 295 300 Gln Asp Leu Ser Ser Pro Arg Leu Ser Gln Leu Cys Ser Gln Gly 305 310 315 Leu Cys Gly Leu Ile Lys Arg Pro Gly Asp Leu Pro Glu Val Leu 320 325 330 Ser Phe His Val Asp Arg Val Leu Gly Leu Arg Arg Ser Leu Pro 335 340 345 Ala Val Ala Arg Arg Phe His Ser Pro Leu Leu Pro Tyr Arg Tyr 350 355 360 Thr Asp Gly Gly Ala Arg Pro Val Ile Trp Trp Ala Pro Asp Val 365 370 375 Gln His Leu Ser Asp Pro Asp Glu Asp Gln Asn Ser Leu Ala Leu 380 385 390 Gly Trp Leu Gln Tyr Gln Ala Leu Leu Ala His Ser Cys Asn Trp 395 400 405 Pro Gly Gln Ala Pro Cys Pro Gly Ile His His Thr Glu Trp Ala 410 415 420 Arg Leu Ala Leu Phe Asp Phe Leu Leu Gln Val His Asp Arg Leu 425 430 435 Asp Arg Tyr Cys Cys Gly Phe Glu Pro Glu Pro Ser Asp Pro Cys 440 445 450 Val Glu Glu Arg Leu Arg Glu Lys Cys Gln Asn Pro Ala Glu Leu 455 460 465 Arg Leu Val His Ile Leu Val Arg Ser Ser Asp Pro Ser His Leu 470 475 480 Val Tyr Ile Asp Asn Ala Gly Asn Leu Gln His Pro Glu Asp Lys 485 490 495 Leu Asn Phe Arg Leu Leu Glu Gly Ile Asp Gly Phe Pro Glu Ser 500 505 510 Ala Val Lys Val Leu Ala Ser Gly Cys Leu Gln Asn Met Leu Leu 515 520 525 Lys Ser Leu Gln Met Asp Pro Val Phe Trp Glu Ser Gln Ser Gly 530 535 540 Ala Gln Gly Leu Lys Gln Val Leu Gln Thr Leu Glu Gln Arg Gly 545 550 555 Gln Val Leu Leu Gly His Ile Gln Lys His Asn Leu Thr Leu Phe 560 565 570 Arg Asp Glu Asp Pro 575 24 327 PRT Homo sapiens misc_feature Incyte ID No 7237245CD1 24 Met Ala Met Glu Glu Arg Lys Pro Glu Thr Glu Ala Thr Arg Ala 1 5 10 15 Gln Pro Thr Pro Ser Ser Ser Thr Thr Gln Ser Lys Pro Thr Pro 20 25 30 Val Lys Pro Asn Tyr Ala Leu Leu Lys Phe Thr Leu Ala Gly His 35 40 45 Thr Lys Ala Val Ser Ser Val Lys Phe Ser Pro Asn Gly Glu Trp 50 55 60 Leu Ala Ser Ser Ser Ala Asp Lys Leu Ile Lys Ile Trp Gly Asp 65 70 75 Ser Tyr Asp Gly Lys Phe Glu Lys Thr Val Trp Ser Gln Pro Gly 80 85 90 Ser Ser Asp Ser Asn Leu Phe Val Ser Ala Ser Asp Asp Lys Thr 95 100 105 Leu Lys Ile Arg Asp Val Ser Ser Gly Lys Cys Leu Lys Thr Leu 110 115 120 Lys Gly His Ser Asn Tyr Val Phe Cys Cys Asn Phe Asn Pro Gln 125 130 135 Ser Ser Leu Thr Val Ser Gly Ser Phe Asp Glu Ser Val Arg Ile 140 145 150 Trp Val Val Lys Thr Gly Lys Cys His Lys Thr Ala Ala His Ser 155 160 165 Asp Pro Val Ser Ala Ile His Phe Asn Arg Asp Gly Phe Leu Ile 170 175 180 Val Ser Ser Ser Tyr Asp Gly Leu Cys His Ile Trp Asp Thr Ala 185 190 195 Ser Gly Gln Cys Leu Lys Thr Leu Thr Asp Asp Asp Asn Pro Trp 200 205 210 Cys Leu Phe Val Lys Leu Ser Pro Lys Gly Gly Tyr Ile Val Ala 215 220 225 Ala Thr Leu Gly Asn Thr Gln Ala Leu Gly Leu Ser Lys Gly Lys 230 235 240 Cys Leu Lys Thr Tyr Thr Gly His Lys Asn Glu Lys Tyr Cys Ile 245 250 255 Phe Ala Asn Phe Ser Val Thr Gly Gly Lys Trp Ile Val Ser Gly 260 265 270 Ser Glu Asp Asn Leu Leu Tyr Ile Trp Asn Leu Gln Thr Lys Glu 275 280 285 Ile Val Gln Lys Leu Glu Gly His Thr Asp Val Val Thr Ser Thr 290 295 300 Ala Cys His Pro Thr Glu Asn Ile Ile Thr Ser Ala Ala Leu Glu 305 310 315 Asn Asp Lys Thr Ile Lys Leu Trp Lys Ser Asp Cys 320 325 25 115 PRT Homo sapiens misc_feature Incyte ID No 7488021CD1 25 Met Trp Met Gly Leu Ile Gln Leu Val Glu Gly Val Lys Arg Lys 1 5 10 15 Asp Gln Gly Phe Leu Glu Lys Glu Phe Tyr His Lys Thr Asn Ile 20 25 30 Lys Met Arg Cys Glu Phe Leu Ala Cys Trp Pro Ala Phe Thr Val 35 40 45 Leu Gly Glu Ala Trp Arg Asp Gln Val Asp Trp Ser Arg Leu Leu 50 55 60 Arg Asp Ala Gly Leu Val Lys Met Ser Arg Lys Pro Arg Ala Ser 65 70 75 Ser Pro Leu Ser Asn Asn His Pro Pro Thr Pro Lys Arg Arg Gly 80 85 90 Ser Gly Arg Phe Pro Arg Gln Pro Gly Arg Glu Lys Gly Pro Ile 95 100 105 Lys Glu Val Pro Gly Thr Lys Gly Ser Pro 110 115 26 311 PRT Homo sapiens misc_feature Incyte ID No 7390973CD1 26 Met Val Asp Leu Ser Val Ser Pro Asp Ser Leu Lys Pro Val Ser 1 5 10 15 Leu Thr Ser Ser Leu Val Phe Leu Met His Leu Leu Leu Leu Gln 20 25 30 Pro Gly Glu Pro Ser Ser Glu Val Lys Val Leu Gly Pro Glu Tyr 35 40 45 Pro Ile Leu Ala Leu Val Gly Glu Glu Val Glu Phe Pro Cys His 50 55 60 Leu Trp Pro Gln Leu Asp Ala Gln Gln Met Glu Ile Arg Trp Phe 65 70 75 Arg Ser Gln Thr Phe Asn Val Val His Leu Tyr Gln Glu Gln Gln 80 85 90 Glu Leu Pro Gly Arg Gln Met Pro Ala Phe Arg Asn Arg Thr Lys 95 100 105 Leu Val Lys Asp Asp Ile Ala Tyr Gly Ser Val Val Leu Gln Leu 110 115 120 His Ser Ile Ile Pro Ser Asp Lys Gly Thr Tyr Gly Cys Arg Phe 125 130 135 His Ser Asp Asn Phe Ser Gly Glu Ala Leu Trp Glu Leu Glu Val 140 145 150 Ala Gly Leu Gly Ser Asp Pro His Leu Ser Leu Glu Gly Phe Lys 155 160 165 Glu Gly Gly Ile Gln Leu Arg Leu Arg Ser Ser Gly Trp Tyr Pro 170 175 180 Lys Pro Lys Val Gln Trp Arg Asp His Gln Gly Gln Cys Leu Pro 185 190 195 Pro Glu Phe Glu Ala Ile Val Trp Asp Ala Gln Asp Leu Phe Ser 200 205 210 Leu Glu Thr Ser Val Val Val Arg Ala Gly Ala Leu Ser Asn Val 215 220 225 Ser Val Ser Ile Gln Asn Leu Leu Leu Ser Gln Lys Lys Glu Leu 230 235 240 Val Val Gln Ile Ala Asp Val Phe Val Pro Gly Ala Ser Ala Trp 245 250 255 Lys Ser Ala Phe Val Ala Thr Leu Pro Leu Leu Leu Val Leu Ala 260 265 270 Ala Leu Ala Leu Gly Val Leu Arg Lys Gln Arg Arg Ser Arg Glu 275 280 285 Lys Leu Arg Lys Gln Ala Glu Lys Arg Gln Glu Lys Leu Thr Ala 290 295 300 Glu Leu Glu Lys Leu Gln Thr Glu Leu Gly Lys 305 310 27 106 PRT Homo sapiens misc_feature Incyte ID No 4890777CD1 27 Met Ile Phe Lys Ile Val Ser Ala Cys Pro Leu Leu Pro Pro Leu 1 5 10 15 Ile Cys Thr Tyr Leu His Pro Thr Cys Ser Ala Ala Ala Leu Ile 20 25 30 Gln Thr Gly Val Glu Asn Gly Leu Gln Asp Leu Met Ile Phe Pro 35 40 45 Gly Ser Leu Cys Ser Gln Ala Pro Ser Glu Lys Gly Ser Trp Gly 50 55 60 Cys Phe Leu Ser Ser Pro Pro Ser Leu Thr Gly Ala Ile Ser Arg 65 70 75 Leu Ser Trp Lys Ser Ser Asp Ala Pro Trp Val Gly Gln Gly Thr 80 85 90 Lys Arg Ser Ser Gln Ile Ser Pro Leu Leu Leu Tyr Arg Ile Arg 95 100 105 Ile 28 121 PRT Homo sapiens misc_feature Incyte ID No 5511444CD1 28 Met Arg Glu Gly Val Arg Glu Arg Pro Thr Gln Ala Ile Val Phe 1 5 10 15 Met Pro Arg Ala Thr Tyr Ala Cys Ser Leu Leu Ser Leu Gly Leu 20 25 30 Phe Ser Val Pro Ser Val Ser Thr Cys Ser Asn Leu Ala Leu Pro 35 40 45 Ala Ile Pro Ser Cys Ser His Leu Leu Glu Ser Phe Pro Leu Leu 50 55 60 Leu Leu Glu Ile Ser Arg Gly Trp Ala Arg Gly Lys Ser Val Thr 65 70 75 Ser Lys Leu Pro Ala Asn Ser Glu Ile Leu Gln Glu Phe Asp Glu 80 85 90 His Gln Gly Leu Gly Ala Trp Lys Ala Gly Gly Pro Gly His Arg 95 100 105 Cys Leu Ser Ser Leu Thr Gly Arg Lys Gln Met Ala Gln Pro Ala 110 115 120 Ser 29 102 PRT Homo sapiens misc_feature Incyte ID No 6104370CD1 29 Met Glu Phe Lys Asp Asn Pro Thr Lys Glu Lys Thr Ser Arg Val 1 5 10 15 Gly Asp Ala Trp Ala Pro Arg Thr Gly Gly Glu Leu His Phe Pro 20 25 30 Gln Met Glu Arg Phe Leu Thr Pro Gly Gln Leu Ser Arg Asn Met 35 40 45 Ala Gly Leu Pro Asp Pro Asn Ser Pro Leu Phe Leu Ala Ala Leu 50 55 60 Val Thr Thr Gly Pro Ser Ser Ser Glu Ala Trp Thr Lys Glu Ala 65 70 75 Leu Ala Arg Thr Gly Phe Gly Gly Gln Trp Val Glu Lys Ser Val 80 85 90 Leu Ala Ala Pro Trp Ser Pro Trp Ile Asn Ile Cys 95 100 30 79 PRT Homo sapiens misc_feature Incyte ID No 7488468CD1 30 Met Pro Leu Arg Lys Leu Ser Phe His Gly Gly Ser Arg Trp Met 1 5 10 15 Pro Val Asn Thr Gly Pro Ala Cys Arg Glu Leu Glu Gly Gly Leu 20 25 30 Leu Ala Ala Pro Arg Pro Asp Thr Asp Phe Ile Ser Asp Cys Gly 35 40 45 Ile Leu Leu Ser Asn Gln Lys Met Leu His Ala Ala Pro Asp Ala 50 55 60 Val Ala Arg Asn His Ala Ala Cys Pro Leu Phe Pro Asp Phe Ser 65 70 75 Ser Val Ala Tyr 31 534 PRT Homo sapiens misc_feature Incyte ID No 7503555CD1 31 Met Ala Ser Trp Leu Arg Arg Lys Leu Arg Gly Lys Arg Arg Pro 1 5 10 15 Val Ile Ala Phe Cys Leu Leu Met Ile Leu Ser Ala Met Ala Val 20 25 30 Thr Arg Phe Pro Pro Gln Arg Pro Ser Ala Gly Pro Asp Pro Gly 35 40 45 Pro Met Glu Pro Gln Gly Val Thr Gly Ala Pro Ala Thr His Ile 50 55 60 Arg Gln Ala Leu Ser Ser Ser Arg Arg Gln Arg Ala Arg Asn Met 65 70 75 Gly Phe Trp Arg Ser Arg Ala Leu Pro Arg Asn Ser Ile Leu Val 80 85 90 Cys Ala Glu Glu Gln Gly His Arg Ala Arg Val Asp Arg Ser Arg 95 100 105 Glu Ser Pro Gly Gly Asp Leu Arg His Pro Gly Arg Val Arg Arg 110 115 120 Asp Ile Thr Leu Ser Gly His Pro Arg Leu Ser Thr Gln His Val 125 130 135 Val Leu Leu Arg Glu Asp Glu Val Gly Asp Pro Gly Thr Lys Asp 140 145 150 Leu Gly His Pro Gln His Gly Ser Pro Ile Gln Glu Thr Gln Ser 155 160 165 Glu Val Val Thr Leu Val Ser Pro Leu Pro Gly Ser Asp Met Ala 170 175 180 Ala Leu Pro Ala Trp Arg Ala Thr Ser Gly Leu Thr Leu Trp Pro 185 190 195 His Thr Ala Glu Gly Arg Asp Leu Leu Gly Ala Glu Asn Arg Ala 200 205 210 Leu Thr Gly Gly Gln Gln Ala Glu Asp Pro Thr Leu Ala Ser Gly 215 220 225 Ala His Gln Trp Pro Gly Ser Val Glu Lys Leu Gln Gly Ser Val 230 235 240 Trp Cys Asp Ala Glu Thr Leu Leu Ser Ser Ser Arg Thr Gly Gly 245 250 255 Gln Ala Pro Pro Trp Leu Thr Asp His Asp Val Gln Met Leu Arg 260 265 270 Leu Leu Ala Gln Gly Glu Val Val Asp Lys Ala Arg Val Pro Ala 275 280 285 His Gly Gln Val Leu Gln Val Gly Phe Ser Thr Glu Ala Ala Leu 290 295 300 Gln Asp Leu Ser Ser Pro Arg Leu Ser Gln Leu Cys Ser Gln Gly 305 310 315 Leu Cys Gly Leu Ile Lys Arg Pro Gly Asp Leu Pro Glu Val Leu 320 325 330 Ser Phe His Val Asp Arg Val Leu Gly Leu Arg Arg Ser Leu Pro 335 340 345 Ala Val Ala Arg Arg Phe His Ser Pro Leu Leu Pro Tyr Arg Tyr 350 355 360 Thr Asp Gly Gly Ala Arg Pro Val Ile Trp Trp Ala Pro Asp Val 365 370 375 Gln His Leu Ser Asp Pro Asp Glu Asp Gln Asn Ser Leu Ala Leu 380 385 390 Gly Trp Leu Gln Tyr Gln Ala Leu Leu Ala His Ser Cys Asn Trp 395 400 405 Pro Gly Gln Ala Pro Cys Pro Gly Ile His His Thr Glu Trp Ala 410 415 420 Arg Leu Ala Leu Phe Asp Phe Leu Leu Gln Val Arg Ser Ser Asp 425 430 435 Pro Ser His Leu Val Tyr Ile Asp Asn Ala Gly Asn Leu Gln His 440 445 450 Pro Glu Asp Lys Leu Asn Phe Arg Leu Leu Glu Gly Ile Asp Gly 455 460 465 Phe Pro Glu Ser Ala Val Lys Val Leu Ala Ser Gly Cys Leu Gln 470 475 480 Asn Met Leu Leu Lys Ser Leu Gln Met Asp Pro Val Phe Trp Glu 485 490 495 Ser Gln Ser Gly Ala Gln Gly Leu Lys Gln Val Leu Gln Thr Leu 500 505 510 Glu Gln Arg Gly Gln Val Leu Leu Gly His Ile Gln Lys His Asn 515 520 525 Leu Thr Leu Phe Arg Asp Glu Asp Pro 530 32 2065 DNA Homo sapiens misc_feature Incyte ID No 7475736CB1 32 gtgcggcgtg tgtgccctgg ggtgcctggc agagacgcgt tgatgggctt ggcagggggt 60 gacgtcggca atgaggattc aaagctctgc gcagaagtgt ccctgaagcc agacgtcttc 120 taactggttg gcctcccctc cagggcagca gacactatgt gcgcgccagc tgcgggatcc 180 agcggcccct tctcagcctc cctgtcactc tcccagctgc ccggagtgtg ccagtccgac 240 caaagcacca ctctcggggc ttcacaccca ccttgcttca accgctccac ctacgcacag 300 ggtaccaccg tcgcgcccag cgcagccccc gccacccggc ctgcgggaga ccagcagagt 360 gtctccaagg cccctaacgt gggctctcgc acgatagctg catggccgca cagcgatgca 420 cgggagggga ctgccccctc cacgaccaac tctgtagcag gtcacagcaa ctccagcgtt 480 ttccccaggg ctgccagcac caccaggacc cagcaccgag gagaacatgc ccccgagctt 540 gtccttgagc ctgatatctc agctgcctcc accccactgg ccagcaagct cctgggcccc 600 ttccctacct cgtgggaccg cagcataagc tcgcctcagc ccggccagag gacacacgcc 660 acaccccaag cccccaaccc gagtctttcc gagggcgaga ttccagtctt gctgctggac 720 gactacagtg aggaggagga agggaggaag gaggaggtgg gaacgcctca ccaggacgtc 780 ccctgtgatt accatccctg caagcacctg cagaccccgt gcgcggagct gcagaggcgg 840 tggcggtgcc ggtgccccgg cctcagcggg gaagacacca tcccagaccc gcccaggctg 900 cagggggtga cggagaccac ggacacgtcg gcgctggtcc actggtgtgc ccccaactcg 960 gtagtgcatg ggtaccagat ccgctactct gcggagggct gggcggggaa ccagtcggtg 1020 gtgggggtca tctacgccac ggcccggcag caccctctgt acgggctgtc gccgggcacc 1080 acctaccgcg tgtgcgtgct ggcggccaac agggcgggct tgagccagcc acggtcttcg 1140 ggctggagga gcccgtgcgc cgccttcacc accaagccca gcttcgcgct cctgctctct 1200 gggctgtgcg ccgccagcgg cctgttgctc gccagcaccg tggtgctgtc cgcatgtctc 1260 tgcaggcggg gccagacgct gggcctgcag cgctgcgaca cgcacctggt ggcctacaaa 1320 aacccggcct ttgatgatta cccgctgggg ctccagaccg tcagttagcc cagcttctgg 1380 gataacgcgt ctcatcgaac tggatctgag cgcaaaaagg aagacacaga cggtcaaaaa 1440 cgaccccatc cgctcctagg gtttctaatt cccgtgaagc cagaatgcct tgagcacaca 1500 tggaacttgc cacactgagt gtctgggtcc aaggaactgc tgccctccct tccttctact 1560 taactctgtt cccagaaacc tgatggtcaa tgccagatcg ctccccactg ccgccaggcc 1620 ttcttgtgtg ttgttggttc atttgcggtt ttcagcagtc agtgcctctg tatccagtag 1680 aatagtgtat ggacgtagga agggatgaaa cagagcaagt gcataaccca gcctcttgat 1740 catgttagaa atccacatcc tcaggtcttt ccagcggaag ctccttcatg gtcaagctct 1800 aagaaacaac gagctctgtt attcaagaaa tcaattccag tggatttcca gttccaattc 1860 ctgagaacta gggtaagggg gagagctaat ggtggcttcc taaggccttc tgggtttatt 1920 agttccattt caggacatga caagaaaatg tactcccggc tttacagtta aaaccagttt 1980 tctgngaaca tttgtcaaac acagggaaag gctgtccttt taagttagtg tttactgcat 2040 ttcacctaag actaaatgga caaat 2065 33 4812 DNA Homo sapiens misc_feature Incyte ID No 859872CB1 33 ctcgagccgg tggtgcatgg cgctcgcatc atggcggctg agtgggcttc tcgtttctgg 60 ctttgggcta cgctgctgat tcctgcggcc gcggtctacg aagaccaagt gggcaagttt 120 gattggagac agcaatatgt tgggaaggtc aagtttgcct ccttggaatt ttcccctgga 180 tccaagaagt tggttgtagc cacagagaag aatgtgattg cagcattaaa ttcccgaact 240 ggggagatct tgtggcgcca tgttgacaag ggcacggcag aaggggctgt ggatgccatg 300 ctgctgcacg gacaggatgt gatcactgtg tccaatggag gccgaatcat gcgttcctgg 360 gagactaaca tcgggggcct gaactgggag ataaccctgg acagtggcag tttccaggca 420 cttgggctgg ttggcctgca ggagtctgta aggtacatcg cagtcctgaa gaagactaca 480 cttgccctcc atcacctctc cagtgggcac ctcaagtggg tggaacatct cccagaaagt 540 gacagcatcc actaccagat ggtgtattct tacggctctg gggtggtgtg ggccctcgga 600 gttgttccct tcagccatgt gaacattgtc aagtttaatg tggaagatgg agagattgtt 660 cagcaggtta gggtttcaac tccgtggctg cagcacctgt ctggagcctg tggtgtggtg 720 gatgaggctg tcctggtgtg tcctgacccg agctcacgtt ccctccaaac tttggctctg 780 gagacggaat gggagttgag acagatccca ctgcagtctc tcgacttaga atttggaagt 840 ggattccaac cccgggtcct gcctacccag cccaacccag tggacgcttc ccgggcccag 900 ttcttcctgc acttgtcccc aagccactat gctctgctgc agtaccatta tggaacgctg 960 agtttgctta aaaacttccc acagactgcc ctagtgagct ttgccaccac tggggagaag 1020 acggtggctg cagtcatggc ctgtcggaat gaagtgcaga aaagtagcag ttctgaagat 1080 gggtcaatgg ggagcttttc ggagaagtct agttcaaagg actctctggc ttgcttcaat 1140 cagacctaca ccattaacct atacctcgtg gagacaggtc ggcggctgct ggacaccacg 1200 ataacattta gcctggaaca gagcggcact cggcctgagc ggctgtatat ccaggtgttc 1260 ttgaagaagg atgactcagt gggctaccgg gctttggtgc agacagagga tcatctgcta 1320 cttttcctgc agcagttggc agggaaggtg gtgctgtgga gccgtgagga gtccctggca 1380 gaagtggtgt gcctagagat ggtggacctc cccctgactg gggcacaggc cgagctggaa 1440 ggagaatttg gcaaaaaggc agatggcttg ctggggatgt tcctgaaacg cctctcgtct 1500 cagcttatcc tgctgcaagc atggacttcc cacctctgga aaatgtttta tgatgctcgg 1560 aagccccgga gtcagattaa gaatgagatc aacattgaca ccctggccag agatgaattc 1620 aacctccaga agatgatggt gatggtaaca gcctcaggca agctttttgg cattgagagc 1680 agctctggca ccatcctgtg gaaacagtat ctacccaatg tcaagccaga ctcctccttt 1740 aaactgatgg tccagagaac tactgctcat ttcccccatc ccccacagtg caccctgctg 1800 gtgaaggaca aggagtcggg aatgagttct ctgtatgtct tcaatcccat ttttgggaag 1860 tggagtcagg tagctccccc agtgctgaag cgccccatct tgcagtcctt gcttctccca 1920 gtcatggatc aagactacgc caaggtgttg ctgttgatag atgatgaata caaggtcaca 1980 gcttttccag ccactcggaa tgtcttgcga cagctacatg agcttgcccc ttccatcttc 2040 ttctatttgg tggatgcaga gcagggacgg ctgtgtggat atcggcttcg aaaggatctc 2100 accactgagc tgagttggga gctgaccatt cccccagaag tacagcggat cgtcaaggtg 2160 aaggggaaac gcagcagtga gcacgttcat tcccagggcc gtgtgatggg ggaccgcagt 2220 gtgctctaca agagcctgaa ccccaacctg ctggccgtgg tgacagagag cacagacgcg 2280 caccatgagc gcacctttat tggcatcttc ctcattgatg gcgtcactgg gcgtatcatt 2340 cactcctctg tgcagaagaa agccaaaggc cctgtccata tcgtgcattc agagaactgg 2400 gtggtgtacc agtactggaa caccaaggct cggcgcaacg agtttaccgt actggagctc 2460 tatgagggca ctgagcaata caacgccacc gccttcagct ccctggaccg cccccagctg 2520 ccccaggtcc tccagcagtc ctatatcttc ccgtcctcca tcagtgccat ggaggccacc 2580 atcaccgaac ggggcatcac cagccgacac ctgctgattg gactaccttc tggagcaatt 2640 ctttcccttc ctaaggcttt gctggatccc cgccgccccg agatcccaac agaacaaagc 2700 agagaggaga acttaatccc gtattctcca gatgtacaga tacacgcaga gcgattcatc 2760 aactataacc agacagtttc tcgaatgcga ggtatctaca cagctccctc gggtctggag 2820 tccacttgtt tggttgtggc ctatggtttg gacatttacc aaactcgagt ctacccatcc 2880 aagcagtttg acgttctgaa ggatgactat gactacgtgt taatcagcag cgtcctcttt 2940 ggcctggttt ttgccaccat gatcactaag agactggcac aggtgaagct cctgaatcgg 3000 gcctggcgat aaagaacaaa gactgtgcct aaaagtggag agccagggga gtgtgggtca 3060 gataagcagc tacagctgca gtttggtgga ttggtggagt atgtgtgtgt gtcagtgctc 3120 agctaagaac tgtagggaag atggatgacc ttcacgcaga actccttttg ggatatacat 3180 gatgcagaaa ggatcctaca tggagagaga cagaactctc tcagctgaca ctctcagaga 3240 ttcctgatgg gctttctctt gaagtccaaa ggcgtctgca ttgtttcctt tctttgccca 3300 tccatgaatg ttctgttttg ttttttttaa taagaattcc ggctgatttt tgtgaggcct 3360 gtttaaattg actttacttt gccttttgtg tttctcaatt ttatctagaa atctttctga 3420 ctttttccat ctcttgcttc aaagtaagag gggaactctc cttgccgact ccaccttata 3480 ggtacatttg gtgttttgca ctgggaagaa ataggatcca tccttagctg aggcttgagg 3540 actgatccag cctctcatgg cttccctcca aagtaactta gggttgaggg atctatatgt 3600 gatgtcaaaa cttactttaa acctctagtt tcgtgctgtc atttattagg ctgggccacc 3660 aaatctttgt ttcaatttat cagaagccaa gtgcatacta gcgtcttgtt tgttgcccat 3720 tgcctatact tttcacctga gatgtgtgag ttggggcctt ttaaaaacta ctgaattgtc 3780 tgagccttga agacatttcc agggagaaga gataatctct catttcaccc acaggctggt 3840 ctaatcataa cctagttaaa gatgtccttg tttaagaacc ccattattta tttttagttt 3900 ttaatataaa ttaacatgtg ggtcattata tttctcctta aatgaggaaa ttttaaattt 3960 tattgatcta acctttgaag ctttaaaaaa ggagaaagag ggtaggggtg ggaaactggc 4020 atactgtgtg tatagcactg ccgattggct aggccactgt gtctctgcta caaattaaag 4080 aaatcctaaa agttttcctt ggtcatagag ttggggaatg acagaatttt tctttgttgt 4140 gaaatgtatg tacagagtag accatctcta gccctgtggt gaaagaggta cactcgaatg 4200 tttgcataaa gcaagtgaca aatgacactg tttaagtcct cttttgtgtc ttagaagatc 4260 attttgaggc tattttcaca ttagagggga taaaagcagt gaagacatgg agtaagtgta 4320 ttttatttta gtaaggaaag gtcagtttaa tcatatatgg gttggttagg ttatctaaaa 4380 atttgtcatc tttctatggt catatgctga tggtagatta tggcagagaa ggaagaggaa 4440 atgacaacca ttttattaat tgtcagtttg atattgagtg actgaatgtc taagaatctc 4500 cagaaaaaaa caggcatcta tcatcctgac ccaaggcata ttttaacata acctgggaga 4560 agagagttaa gtacaagtta aaaaaaattc tgccctagtt ttgagaaagc ctggctggaa 4620 ttctgactgt cttacataca tatgtgcaag gttagcctgc aagattctag tttttattta 4680 ccagtgtgcc agaatctgaa acaagctact gggagggaag gtattgtcct ttagtaaaat 4740 tccctgtatt tcagtgtaat caagtactca agcaggtgct ttttcgagac agaatctccc 4800 tctgtgcccg gg 4812 34 971 DNA Homo sapiens misc_feature Incyte ID No 1893683CB1 34 gcctcccggg ccgtaagtac cggcgtggcg gcgcctcagc ccggcctggg cgagccctgg 60 gtgctccgcc gggcagctca cggcgccccg tatggcctgg ggatcctaag aggccctgtg 120 acccccctcg cctggtctcc ctctcacccc tggagggttg ccgcagctcc ggggcccccg 180 ggcaggaagg gcgcactggt cgtcccggga gaggggtctg agcagagggc ggggtgcagg 240 cggaatggcc ctcgtgccct atgaggagac cacggaattt gggttgcaga aattccacaa 300 gcctcttgca actttttcct ttgcaaacca cacgatccag atccggcagg actggagaca 360 cctgggagtc gcagcggtgg tttgggatgc ggccatcgtt ctttccacat acctggagat 420 gggagctgtg gagctcaggg gccgctctgc cgtggagctg ggtgctggca cggggctggt 480 gggcatagtg gctgccctgc tggaaaacac tggacaaatg caaactgagg gatattctaa 540 aagaaaacag atcactactc ttcaaaagtt acaaggccat caaagacaag gaaacaaact 600 ttcacagact gaaggagact ataattaaat gcgatatggt acccaaactg gattatgtaa 660 gtaaaaaaac tggggaaata aaatgtataa ttcagttaat ggtattatac caatgtactt 720 ttatttttga taaatgtacc ctggttatgt aatatactaa gattagagaa agctggatga 780 agggtatccg gaactctgta tttttacaac tcctttgtaa gtttaaaatt acttaaaaat 840 atattaaaaa tgtatattta cctttgtact ggtttgagta aaaaaactga ctttagaatg 900 ttaacatttt agatggtgaa attagaagta attcaatttt taggtaatgt ttcttaattt 960 acttataatg a 971 35 2064 DNA Homo sapiens misc_feature Incyte ID No 2824347CB1 35 ttcggctcga ggtttgtatg gggctactag ctcacatgcg ggatcagaat ggtgtgaatg 60 acagccgcac tgtgtcatga aggtggtggt ggtttccgca caagagacca aataagaaga 120 aagctgagag aggggggaaa cgtttttgga tgacaaagga tgggtttcca tttaattacg 180 cagctgaaag gcatgagtgt ggtgctggtg ctacttccta cactgctgct tgttatgctc 240 acgggtgctc agagagcttg cccaaagaac tgcagatgtg atggcaaaat tgtgtactgt 300 gagtctcatg ctttcgcaga tatccctgag aacatttctg gagggtcaca aggcttatca 360 ttaaggttca acagcattca gaagctcaaa tccaatcagt ttgccggcct taaccagctt 420 atatggcttt atcttgacca taattacatt agctcagtgg atgaagatgc atttcaaggg 480 atccgtagac tgaaagaatt aattctaagc tccaacaaaa ttacttatct gcacaataaa 540 acatttcacc cagttcccaa tctccgcaat ctggacctct cctacaataa gcttcagaca 600 ttgcaatctg aacaatttaa aggccttcgg aaactcatca ttttgcactt gagatctaac 660 tcactaaaga ctgtgcccat aagagttttt caagactgtc ggaatcttga ttttttggat 720 ttgggttaca atcgtcttcg aagcttgtcc cgaaatgcat ttgctggcct cttgaagtta 780 aaggagctcc acctggagca caaccagttt tccaagatca actttgctca ttttccacgt 840 ctcttcaacc tccgctcaat ttacttacaa tggaacagga ttcgctccat tagccaaggt 900 ttgacatgga cttggagttc cttacacaac ttggatttat cagggaatga catccaagga 960 attgagccgg gcacatttaa atgcctcccc aatttacaaa aattgaattt ggattccaac 1020 aagctcacca atatctcaca ggaaactgtc aatgcgtgga tatcattaat atccatcaca 1080 ttgtctggaa atatgtggga atgcagtcgg agcatttgtc ctttatttta ttggcttaag 1140 aatttcaaag gaaataagga aagcaccatg atatgtgcgg gacctaagca catccagggt 1200 gaaaaggtta gtgatgcagt ggaaacatat aatatctgtt ctgaagtcca ggtggtcaac 1260 acagaaagat cacacctggt gccccaaact ccccaaaaac ctctgattat ccctagacct 1320 accatcttca aacctgacgt cacccaatcc acctttgaaa caccaagccc ttccccaggg 1380 tttcagattc ctggcgcaga gcaagagtat gagcatgttt catttcacaa aattattgcc 1440 gggagtgtgg ccctctttct ctcagtggcc atgatcctct tggtgatcta tgtgtcttgg 1500 aaacgctacc cagccagcat gaaacaactc cagcaacact ctcttatgaa gaggcggcgg 1560 aaaaaggcca gagagtctga aagacaaatg aattcccctt tacaggagta ttatgtggac 1620 tacaagccta caaactctga gaccatggat atatcggtta atggatctgg gccctgcaca 1680 tataccatct ctggctccag ggaatgtgag atgccacacc acatgaagcc cttgccatat 1740 tacagctatg accagcctgt gatcgggtac tgccaggccc accagccact ccatgtcacc 1800 aagggctatg ggacagtgtc tccagagcag gacgaaagcc ccggcctgga gctgggccga 1860 gaccacagct tcatcgccac catcgccagg tcggcagcac cggccatcta cctagagaga 1920 attgcaaact aacgctgaag ccaactcctc actggggagc tccatggggg ggagggaggg 1980 ccttcatctt aaaggagaat gggtgtccac aatcgcgcaa tcgagcaagc tcatcgttcc 2040 tgttaaaaca tttatggcat agag 2064 36 1221 DNA Homo sapiens misc_feature Incyte ID No 5055878CB1 36 cagaggaaca gttggccaag gaagtcagct tctcagagct caagagtaga tctgagttta 60 actcattaaa gatggcatgg aagagcagtg tcataatgca aatgggaaga tttcttctct 120 tagtaatttt atttctgcca cgtgagatga caagttctgt tttaactgtg aatggtaaaa 180 ctgagaacta tatcctggat actacacctg gctcccaagc atctctgata tgtgctgttc 240 aaaaccacac cagagaggaa gaactgctct ggtaccgaga ggaggggaga gtggatttga 300 aatctggaaa caaaatcaat tccagctctg tctgtgtctc ttccatcagt gaaaatgaca 360 acggaatcag ctttacctgc aggctgggga gggatcagtc cgtgtccgtt tcggtggtgc 420 tgaatgttac ttttcctcct ctcctaagtg gaaacgactt ccaaacagtt gaggaaggca 480 gtaatgtgaa gttggtttgc aatgtgaaag ccaaccccca ggctcaaatg atgtggtaca 540 aaaacagtag tctcctcgat ttagagaaaa gccgtcacca aatccaacag acaagtgagt 600 cttttcagct gtcaatcacc aaagtcgaga agcctgacaa cggaacctac agttgtattg 660 caaagtcatc tctgaaaacg gagagcttgg actttcacct gattgttaaa gataaaactg 720 tgggtgtacc aatagagccc attattgctg catgtgttgt gatctttctg acattgtgct 780 ttggactgat tgctagaaga aagaaaataa tgaagctctg catgaaggat aaagaccctc 840 acagtgaaac agctctatga gaaagctgag atgccatcga atacagagag agttttgcat 900 caggacctcc acaatttatg tagtcccatc tgtatttatt gctattatta aattcactcc 960 tgtcactcct gtttcattaa tcacttaaca gtagttgtta ggactaattt gatacacttg 1020 tggaacattt ttatggaaag agctattaag aatgaaaagt aagattttgt taagtcttct 1080 ccttgaagta tatgttaatt aattgagatt tgttccaaat aggttggtaa tcatttactg 1140 tttagtgtgt tttttttcta ggtaggagat acttgggtct cacaaattgg tgcaaagcca 1200 aaaaaaaaaa aaaagggaag a 1221 37 1030 DNA Homo sapiens misc_feature Incyte ID No 7473596CB1 37 tacctccaag cttggttacc gagcttcgga tccaacttag ttacggtcct gccagtttgc 60 tggaattcgc ccttaataca ggattccaga ccctccattt tagtgagatt attattgctg 120 aatgatgccc atttcaaatt ttccaatttt tctaaatttg tgatttcaaa aagatgttgt 180 ccatctaaat ttaaggcagt tatctgtaga ataatttaca ttgtatgtta tttctaaatc 240 ttataaattc agtcaatgtt aataacattt taaaaagcta atgaaataat tcaaatgtga 300 taaatagata tcaaaagaat tccttcagga gctaaagata ttgtgaagct gtcagtttac 360 agaaaagtaa aatttgacga gattataact ccaagaagga cttatatggt attaaggaca 420 ctgcgatgtg ctagagtccc attacagtaa tggacttgtc ccagctgctg ggagtgcttc 480 tggcagagtc ttcagctgtc agtccctgca gggactgcct tgctgtagac agctgccaag 540 gtcactctcc ttcccaggtt ggccctcagc cagtgatgga agcctataaa ggcctgacca 600 tctcagccca acttaggaca aatttaaagg gccattctaa ctccactaac tccagaactg 660 cctgtgggtc agccaaagct gtcactgggc cttcatttgc agctcaatat ctatatatat 720 cttgtaataa aagtaatgcc agtaatgtct cccattttct gggagcagct tcacttagcc 780 cagtttctat gtttggcaag aggtataagg acacctaatg tagcaagaag ctgcaagtgt 840 tctataacct tttcccttat ccttggctga attctgacca gctcccctac tcccttgtca 900 ggatacctga ctcttgctgt ctgaattttg gcttgatctc tggctctgag cctttaaagt 960 ttgctttcct attctgacat gttatcagaa tcttgcctat tctgacatgt tatcagaata 1020 cggaattaga 1030 38 1795 DNA Homo sapiens misc_feature Incyte ID No 7497718CB1 38 gaaaatcagc ataaagaagc ccaataatgt ctgcctgagt ttcccctatg atgactttgg 60 tacttttggg aaacattaag tatgaagtta tttcaaaata attttttggt gcctctgctt 120 ggcgatgcct taaactctgg gtaagagaaa caccaggtgc ctgtcaggag atggcctttt 180 ccaggtttct ggttaagcta caaacagcta actggctgct gtcatcaaaa taaaagcttt 240 ctgaaggtgg aggcatctga tacccagagt gctgctatca gccggcacgg tgggccgctg 300 gtggcaggag cgtcgagaag gccagctcgc ttcctatctg ggattcagaa tcagctatgg 360 aaacttgaga gacctagaga aaataacttc tttcactttg aactgattct ttgcttcata 420 agaaaagtat tatccagcca caaaaatggt caaaattcag atctacaaaa gcctgtcagg 480 cagaaactga ccccacttag gccacgccaa tgagcaagtc atcaaagcag ccaagacagg 540 tcctgtgggg gccacccatg cacagggccc agcctcgggt cctaaccccg cctatgcttt 600 ccgccaccat aaagaggccc atctgggtaa gacctgtccc gcctgctgtg gggtattagg 660 gcagatgggg tctgaggggt ctgagggctc tgagagcagc tggcagctca aggacatccg 720 gagttggagg atggagcaat gcaggccctt gtggtaaaga cagtcctgca gccgcgcagg 780 cagggatgct gcaagtggag tgccaggcgg gtgcggagcc ctgtgggact gtggaggggt 840 cagagggaag ccaggatttt ggggtctctg agagtttgga gaaggggaag aagattaaag 900 cttgtttcaa aagtttctaa tcaggtgggc agggccaagg gtggctgtgg ggtgagaccc 960 atgactcagg gtggcccact gttactctat tgatttttgg gcgttttttt tccaaattga 1020 ttattcttgc tgaatgagac ctgagtcctt gactgtcccc ttaaagccac ctgacttgtt 1080 ttcagttcca ctggcctgtc gggctgtttt ctactcaact ccactcttgc ttgtctgccc 1140 tccctgcctg gggcccagcc agcagtcagc tcaagggcca gatgaattgg gtggctgtgc 1200 tctgcccact gggcatcgtg tggatggtgg gtgaccagcc ccctcaggtg ctcagccagg 1260 cctcaagcct tgctgtgtac ctcagagcag ctccgtaccc tgatgtcaca gcaaagaaac 1320 ttagacatga cacaaactgt ggcttcccaa ggcagcaaag aatggccagg ggtcatgagg 1380 gccgtgcccc acttttggac agacctactc taaagtcacg ctacctgcgt gcaaatcata 1440 aaatcaacac ttttgaggag atcacagcta tgccttcgca acactgggtg ccaggggtgg 1500 ggctggcctg ccccccaacc ccatctgctg aggagtggct gacaagcgga cacccaccag 1560 ggtgccactc gcttgtgcct ggggaagcaa atgtgctcgc ttgacccgtc tgatgtgctg 1620 ccgtgggcac ttgactgaga gtggcagggc actaggctaa cccaaagtga cacatgcctg 1680 gcgggatgtt cagtctctgt aaacccatat ggtttttttt ttttctttcc tttaaaaaaa 1740 atttctagct ccatctagcg aaagcggaaa taaaaagtat taggccaaaa aaaaa 1795 39 2698 DNA Homo sapiens misc_feature Incyte ID No 7498077CB1 39 caggactccc aggacagaga gtgcacaaac tacccagcac agccccctcc gccccctctg 60 gaggctgaag agggattcca gcccctgcca cccacagaca cgggctgact ggggtgtctg 120 ccccccttgg gggggggggc agcacagggc ctcaggcctg ggtgccacct ggcacctaga 180 agatgcctgt gccctggttc ttgctgtcct tggcactggg ccgaagccca gtggtccttt 240 ctctggagag gcttgtgggg cctcaggacg ctacccactg ctctccggtg agtctggaac 300 cctggggaga cgaggaaagg ctcagggttc agtttttggc tcagcaaagc cttagcctgg 360 ctcctgtcac tgctgccact gccagaactg ccctgtctgg tctgtctggt gctgatggta 420 gaagagaaga acggggaagg ggcaagagct gggtctgtct ttctctggga gggtctggga 480 atacggagcc ccagaaaaag ggcctctcct gccgcctctg ggacagtgac atactctgcc 540 tgcctgggga catcgtgcct gctccgggcc ccgtgctggc gcctacgcac ctgcagacag 600 agctggtgct gaggtgccag aaggagaccg actgtgacct ctgtctgcgt gtggctgtcc 660 acttggccgt gcatgggcac tgggaagagc ctgaagatga ggaaaagttt ggaggagcag 720 ctgactcagg ggtggaggag cctaggaatg cctctctcca ggcccaagtc gtgctctcct 780 tccaggccta ccctactgcc cgctgcgtcc tgctggaggt gcaagtgcct gctgcccttg 840 tgcagtttgg tcagtctgtg ggctctgtgg tatatgactg cttcgaggct gccctaggga 900 gtgaggtacg aatctggtcc tatactcagc ccaggtacga gaaggaactc aaccacacac 960 agcagctgcc tgccctgccc tggctcaacg tgtcagcaga tggtgacaac gtgcatctgg 1020 ttctgaatgt ctctgaggag cagcacttcg gcctctccct gtactggaat caggtccagg 1080 gccccccaaa accccggtgg cacaaaaacc tgactggacc gcagatcatt accttgaacc 1140 acacagacct ggttccctgc ctctgtattc aggtgtggcc tctggaacct gactccgtta 1200 ggacgaacat ctgccccttc agggaggacc cccgcgcaca ccagaacctc tggcaagccg 1260 cccgactgcg actgctgacc ctgcagagct ggctgctgga cgcaccgtgc tcgctgcccg 1320 cagaagcggc actgtgctgg cgggctccgg gtggggaccc ctgccagcca ctggtcccac 1380 cgctttcctg ggagaatgtc actgtggaca aggttctcga gttcccattg ctgaaaggcc 1440 accctaacct ctgtgttcag gtgaacagct cggagaagct gcagctgcag gagtgcttgt 1500 gggctgactc cctggggcct ctcaaagacg atgtgctact gttggagaca cgaggccccc 1560 aggacaacag atccctctgt gccttggaac ccagtggctg tacttcacta cccagcaaag 1620 cctccacgag ggcagctcgc cttggagagt acttactaca agacctgcag tcaggccagt 1680 gtctgcagct atgggacgat gacttgggag cgctatgggc ctgccccatg gacaaataca 1740 tccacaagcg ctgggccctc gtgtggctgg cctgcctact ctttgccgct gcgctttccc 1800 tcatcctcct tctcaaaaag gatcacgcga aagggtggct gaggctcttg aaacaggacg 1860 tccgctcggg ggcggccgcc aggggccgcg cggctctgct cctctactca gccgatgact 1920 cgggtttcga gcgcctggtg ggcgccctgg cgtcggccct gtgccagctg ccgctgcgcg 1980 tggccgtaga cctgtggagc cgtcgtgaac tgagcgcgca ggggcccgtg gcttggtttc 2040 acgcgcagcg gcgccagacc ctgcaggagg gcggcgtggt ggtcttgctc ttctctcccg 2100 gtgcggtggc gctgtgcagc gagtggctac aggatggggt gtccgggccc ggggcgcacg 2160 gcccgcacga cgccttccgc gcctcgctca gctgcgtgct gcccgacttc ttgcagggcc 2220 gggcgcccgg cagctacgtg ggggcctgct tcgacaggct gctccacccg gacgccgtac 2280 ccgccctttt ccgcaccgtg cccgtcttca cactgccctc ccaactgcca gacttcctgg 2340 gggccctgca gcagcctcgc gccccgcgtt ccgggcggct ccaagagaga gcggagcaag 2400 tgtcccgggc ccttcagcca gccctggata gctacttcca tcccccgggg actcccgcgc 2460 cgggacgcgg ggtgggacca ggggcgggac ctggggcggg ggacgggact taaataaagg 2520 cagacgctgt ttttctaccc atgtggccca cacgcgtctc cgtttcagtg gcggggctgg 2580 caaacgtcgt tccctagccc cgcggccctt taaagcccgg acaggtgcag ctcggtgccg 2640 cctctggttg gctggcgtgg tggtgacgta attggcacat tggccccgtc gcccattc 2698 40 1969 DNA Homo sapiens misc_feature Incyte ID No 1633319CB1 40 aaagagtcaa ggcttagtaa tattcctgaa ttcctgaagg agttaagaaa ggaaaaggac 60 aagcgggggt ctaaacgaga gcacgaaccc tcagcgtatg acggctccag gctccggggg 120 aaagtccttt agccatccat cccaaaatta agcacgctgg gagctggagt cacagcagtg 180 ataaaacgaa caatgattct ggttcctact gactgacagg agaggtttaa gggtctctca 240 ctctccgggg agcccctttc cttcctggct gcggagggcg gagcccgaga gaggcacgca 300 tgcgcaatgc aacgtctgcc ttaggcccgg aacttcggtg cctgggcgca gcggtgcacc 360 cggacccgga acattctcag gcgaaagtgt ctcttgcgtg cgtgggccgg aggttagtgt 420 gcggggcccg ccgggcggtt gaaaagtccg agagaatcag gatggaggcc gtggcgacgg 480 cgacggcggc gaaggaaccc gataagggct gcatagagcc tggacctggg cactggggtg 540 agctgagccg gacaccagtc ccatctaaac cccaggacaa agtggaagca gctgaggcaa 600 caccagtggc cctggacagt gacacctccg gggctgaaaa tgcagcagtg agtgctatgc 660 tgcacgctgt agccgccagc cgcctgcctg tttgcagcca gcagcagggt gaacccgact 720 tgacagagca tgagaaagtg gccatcctgg cccagctgta ccacgagaag ccactggtgt 780 tcctggagcg cttccgcaca ggcctccgtg aggagcatct ggcctgcttt ggccacgtgc 840 gtggcgacca ccgtgcagac ttctactgtg ctgaggtggc ccggcagggc actgcccggc 900 cccgcaccct gcgtacccgc ctgcgtaacc ggcgctatgc tgccctgcga gagctgatcc 960 aagggggcga gtacttcagt gatgagcaga tgcggttccg ggcccccctg ctatatgagc 1020 agtacatcgg gcagtatctc acccaggagg agctcagtgc ccgcacccca acccaccagc 1080 cccccaagcc cgggtccccc gggagacctg cttgcccgct ctccaacttg ctgctccagt 1140 cctacgagga gcgggagcta cagcagcgtc tgctccaaca gcaggaggag gaggaggcct 1200 gcttggagga agaggaagag gaggaggaca gtgacgagga agaccagagg tcaggcaagg 1260 actcggaggc ctgggttccc gactcggagg agaggctgat cctgcgagag gagttcacca 1320 gccgcatgca ccagcgcttc ctagatggca aggacgggga ctttgactac aggtgctcct 1380 gtgcctccac ctccccatcc cccagcccag catcccacgg cctttggtca catgcagagc 1440 ccttaacaag ctgtgggggt ctccctttgt ggagctacaa ggccccaaaa cagttccagg 1500 atgtggggtt gaacagccaa aggaagaggc tgggtgacct cggactagcc ttgtccatct 1560 cagaccctca gtctcctcac ctctaaggca ggggatggac agggatgaca tatagctcag 1620 tatcaatgaa accctgaaac acttccctcc tggcaatggc agaggctact accccaagcc 1680 ccccaagtct ccctaggaag cccaacctct tccgcttcac cttggacctc ctcatgctgc 1740 aggaagtaac ccctggcaaa gttcatgccc ggcatggagg ggcctgcact ggctgccccc 1800 acagttacag ttgttcattt ctccagtagc accccagggc tgagacacgt gggccacctg 1860 ctttggaaaa ggacccagga gagtgatgtg tcagtcaaaa aaaaaaaaaa aaaaaaaaaa 1920 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaa 1969 41 1544 DNA Homo sapiens misc_feature Incyte ID No 1712631CB1 41 ctagcgcgcg agagagagcg agagcgcgcg cgccgatgac gtcacgctcg gcgtctcggc 60 catcttagct gtagatagag gcggcaacct cggaagtgcg gagcgggtgg gcctatatag 120 atgttgaggt gcggaggccg tgggcttttg ttgggcctgg ctgtagccgc agcagcggta 180 atggcagcac ggcttatggg ctggtggggt ccccgcgctg gctttcgcct tttcataccg 240 gaggagctgt ctcgctaccg cggcggccca ggggacccgg gcctgtactt ggcgttgctc 300 ggccgtgtct acgatgtgtc ctccggccgg aggcactacg agcctgggtc ccactatagc 360 ggcttcgcag gccgagacgc atccagagct ttcgtgaccg gggactgttc tgaagcaggc 420 ctcgtggatg acgtatccga cctgtcagcc gctgagatgc tgacacttca caattggctt 480 tcattctatg agaagaatta tgtgtgtgtt gggagggtga caggacggtt ctacggagag 540 gatgggctgc ccaccccggc actgacccag gtagaagctg cgatcaccag aggcttggag 600 gccaacaaac tacagctgca agagaagcag acattcccgc cgtgcaacgc ggagtggagc 660 tcagccaggg gcagccggct ctggtgctcc cagaagagtg gaggtgtgag cagagactgg 720 attggcgtcc ccaggaagct gtataagcca ggtgctaagg agccccgctg cgtgtgtgtg 780 agaaccaccg gcccccctag tggccagatg ccggacaacc ctccacacag aaatcgtggg 840 gacctggacc acccaaactt ggcagagtac acaggctgcc caccgctagc catcacatgc 900 tcctttccac tctaagccgt agcctcttct gttaataaca cacagagagc tctgccaagc 960 acctgagtag gcccttgaca cttgtgtgcc ctgggatgcc tcctggcgcg aatcaggagg 1020 ttctggaagg actctggcta tattctgcaa atgtggctca tgccccttac cgtggctcgg 1080 cgttgtggtg cctgagggac agccggccac ctgcccagta ctggtcagct tttcaacact 1140 attccctttg acctactggc catcttcctc acagccctca gatatcaacg ggcacaaata 1200 agaccaactc aatttccact tgaatttaca accaaaagcc tgctgagttg attacagctg 1260 ggccaataca gtacgaggca ataacaaatt agtgtgggtt gattctggaa ttggaaaagc 1320 ttttgcttgt atggatacag caaatccaga tgtctctgaa caaagcaaca atttaaagca 1380 acgacatttt ctgtccttta agcacttaaa atcaggtgtg gtgtgttttc aaaggcagaa 1440 gtctgcattt tgagcaaaag gtggcttccc agctctaaca aggtaactgg ttagcatgac 1500 attaaagctt gggcaaggct tcaaacttaa aaaaaaaaaa aaaa 1544 42 4596 DNA Homo sapiens misc_feature Incyte ID No 1795426CB1 42 gccgagccca cgctggctgg ggccggggtg ccggcgcgct cgggactcgt ctcagcagtc 60 gctcacggtc tttgtgtctt ctcttccgcc cctttccctg cctgccgcct ccggccgcca 120 cgatgcccct gcgccccgct gctgccgccg cggactggct gcgccggctg cgcgctgctt 180 gctgcggcgg tggtggcgcc ccatctgcta cacgggcctg aagaaggaag aagaggaagc 240 gaagcgcgcc ccccggccca tgccgcagcc acgggcccag acccgccacg gcgcccgcgc 300 cgccgccctc gccggagccc acgagacctg catggacggg catgggcttg agagcagcac 360 cttccagcgc cgccgctgcc gccgccgagg ttgaacagcg ccgccgcccc gggctctgcc 420 ccccgccgct ggagctgctg ctgctgctgc tgttcagcct cgggctgctc cacgcaggtg 480 actgccaaca gccagcccaa tgtcgaatcc agaaatgcac cacggacttc gtgtccctga 540 cttctcacct gaactctgcc gttgacggct ttgactctga gttttgcaag gccttgcgtg 600 cctatgctgg ctgcacccag cgaacttcaa aagcctgccg tggcaacctg gtataccatt 660 ctgccgtgtt gggtatcagt gacctcatga gccagaggaa ttgttccaag gatggaccca 720 catcctctac caaccccgaa gtgacccatg atccttgcaa ctatcacagc cacgctggag 780 ccagggaaca caggagaggg gaccagaacc ctcccagtta ccttttttgt ggcttgtttg 840 gagatcctca cctcagaact ttcaaggata acttccaaac atgcaaagta gaaggggcct 900 ggccactcat agataataat tatctttcag ttcaagtgac aaacgtacct gtggtccctg 960 gatccagtgc tactgctaca aataagatca ctattatctt caaagcccac catgagtgta 1020 cagatcagaa agtctaccaa gctgtgacag atgacctgcc ggccgccttt gtggatggca 1080 ccaccagtgg tggggacagc gatgccaaga gcctgcgtat cgtggaaagg gagagtggcc 1140 actatgtgga gatgcacgcc cgctatatag ggaccacagt gtttgtgcgg caggtgggtc 1200 gctacctgac ccttgccatc cgtatgcctg aagacctggc catgtcctac gaggagagcc 1260 aggacctgca gctgtgcgtg aacggctgcc ccctgagtga acgcatcgat gacgggcagg 1320 gccaggtgtc tgccatcctg ggacacagcc tgcctcgcac ctccttggtg caggcctggc 1380 ctggctacac actggagact gccaacactc aatgccatga gaagatgcca gtgaaggaca 1440 tctatttcca gtcctgtgtc ttcgacctgc tcaccactgg tgatgccaac tttactgccg 1500 cagcccacag tgccttggag gatgtggagg ccctgcaccc aaggaaggaa cgctggcaca 1560 ttttccccag cagtggcaat gggactcccc gtggaggcag tgatttgtct gtcagtctag 1620 gactcacctg cttgatcctt atcgtgtttt tgtaggggtt gtcttttgtt ttggtttttt 1680 attttttgtc tataacaaaa ttttaaaata tatattgtca taatatattg agtaaaagag 1740 tatatatgta tataccatgt atatgacagg atgtttgtcc tgggacaccc accagattgt 1800 acatactgtg tttggctgtt ttcacatatg ttggatgtag tgttctttga ttgtatcaat 1860 tttgttttgc agttctgtga aatgttttat aatgtccctg cccagggacc tgttagaaag 1920 cactttattt tttatatatt aaatatttat gtgtgtgctt ggttgatatg tatagtacat 1980 atacacagac atccatatgc agcgtttcct ttgaaggtga ccagttgttt gtagctattc 2040 ttggctgtac cttcctgccc tttcccattg ctactgattt gccacggtgt gcagctttta 2100 ctcgccacct tccggtggag ctgcctcgtt cctttgaact atgccctcac ccttctgccc 2160 tcacttgatt tgaaagggtc gttaactctc ccttacaggt gctttgactc ttaaacgctg 2220 atcttaagaa gctctcttca tctaagagct gttacttttt cagaaggggg ggtattattg 2280 gtattctgat tactctcaat tctaattgtt atatatttga gcccatacag tgtattaggt 2340 tgaaccatag aaactgctat tctcgtaggt caaaagggtc tagtgatgga agttttgtag 2400 ataagtacca ggcatctcag taactcctag actttttctc atcccatgcc ccgttttaaa 2460 ttgtcagttt tccctctgac tcttctgtgt taaaacatga aactataaat ttagtaatta 2520 tcatgccttg ctctttttaa tctatatgac tgatgcaagc ccctcttctt aaccgtttct 2580 tggctttgag cccagaaaca cagctctccc tgtctccaac tccagtaagc cctcctcagc 2640 ctcaccttac gaatccaaag aactggggtt tgttaggttc tttctctaat gtagaggccc 2700 agatcccatc acaaagtttt tcattcttcc ttgtccacca tgatcttcat cacagtcttt 2760 gatatgtctg catgcaaagt ggaacagagt tgggcggcaa tgacagaaga gcttccttgg 2820 cctgactcgg tgtgcggcca cttcggcact gcttaatcca gatattcttg ttaactaagc 2880 attgtgcttc ccaggtggtc tgaagtcagg tactctctct ctcaacacct gtagttgaat 2940 atgatttggt cagttgctcg ttgtaacttg gagaaattcc tataaagtaa gatctccttg 3000 cctcttccat ccattgttgg cacccccttg caaaaggaaa agaacagcaa aagtcaggag 3060 cagtaatctg agaaagttaa ctccaggata ggtaggtttc tattgttata gctagatgta 3120 aatctttagt tccaagaagt gatagagttt ctgctttaat aatttgttga taagtttaca 3180 taaacagaaa taaaagatac tatctttacc gtagtagttc aggccaagat tatgcttagt 3240 tttagttctc caggtagtta cttttgccat gtcctattga tcagtgacac tgccagaggc 3300 ccataccggc aagaggaaga ggacgtcatt ttgtaaagtt taacttctta gcgaactgat 3360 gtgccaccca gtcacagagt ggagttgtga attcatgtag aggtggcaaa cctctacctt 3420 gtgttgatga gagaataatc ttgggcagtc tgggaaaata aggaaggcat ctccttctta 3480 ctcatggaga ttcaactata gagagttgaa acctaaaccc gccttccttt tatagaagct 3540 ggactagaga cggactgacc atcagctctg aactgtggct ttttttgttc acctatgatg 3600 ccatgtacca aattcagaag ctatcgttaa taatttgttt tataattgag tagtacaagc 3660 gaggaaaaaa tacggaggat aaccactatt tttgtgcaaa taatatgaaa gtgaagtaaa 3720 agcaatagaa gaaatttcta taggatctgg gtttagagtg tgtatcatta ataaatatac 3780 ctttgctctt ttcagggaaa ataacaacca cccttactga tagttgggaa aagaagattg 3840 ggttattttg ccatatcatt tagctggaag tgacatttaa aagcaccctg catcactagt 3900 aatagtgtat tttgctattc tgcccttgta atcggtgtcc ctgtaaaaca atccccacag 3960 attactttca gaaatagatg tatttctcta cgtaagggcc aggtttattt tctccttttt 4020 tgagatttct agaaaaaatg ctgcttgcac atgttggttc ttgaaacctt agctagaaga 4080 atttcaggtc ataccaacat gtggataggc tatagctgtt cagaggtctc ctgggggagc 4140 ttaaaacggg ggaaacactg gttttcacag atgctccaca tggctgtctt taaaagactc 4200 aaaacttttt tttgtcctct ttgttatgct tggaagctcc ccccccccca acagtgtgtc 4260 gagtctttgc aaagaaacct ttagatgtgg ttcatagata tatgaatacg tatctgtgta 4320 aaacagtgag tgtgcagtgt gtaaatactt taaattatta tgctagaaaa ataaagttac 4380 ataccttgct gtggaccttg tggagaacct ggacagcctg ccccccaaag ttccacagcg 4440 ggaggcctcc ctgggtcccc cgggagcctc cctgtctcag accggtctaa gcaagcggct 4500 ggaaatgcac cactcctctt cctacggggt tgactataag aggagctacc ccacgaactc 4560 gctcacgaga agccaccagg ccaccactct caaaag 4596 43 1073 DNA Homo sapiens misc_feature Incyte ID No 1329584CB1 43 gccacgtgaa cctgaggcat gaaagtcctt gccagcccca cagggtactg ctccagctgc 60 cgcctccagg ggcctgtccc tctgcaggtc cccagctctg tctctccctc cctctcctgc 120 tcaggctgag acttgtgttt tcccggggaa gccaactcca agaccctctc tcctgagtcc 180 ctgcccggat aacaggctct ctccttggaa tgttttccct acaatcctca tgagaacacg 240 ctatgtgacc ttgagcaagt tactcaacct ctccatgcct ctgactcctc taccaagagg 300 ggataataac atacctacct ccctggaact gtgctgtgag gcctcaatgg aaaccaagca 360 aagcacttag aaccctgcct gcctaagtgt tagtaatggc tgcccagacc acctgtccag 420 cggttagagc tcaggaccca tgtgacaggc tctgaagctg cagccccaca acggatggct 480 acctctgcac agggaaagac ctggatgctc tattcattca acagaataca gaaggcactg 540 ggaatagagt gaacaatgac aaccaatgca cagctgccca caaggtgggc tcctggggga 600 gggtcatccc tctgagaaga gggcggcacc aagacccaca cacctgaaaa atgtggtact 660 tcatgtcgct gatctcgatg gtcttgctgc tgtccccatc ctgttctgat ttattggtca 720 ttagtgtctt gaacctggag caaaggagac aaagcaaggt gggttttgaa ccttttactt 780 caccactgtg tggcgatggc accatctgtc acctgaccgg ctaccacaag acggaacatt 840 ttaaaaatta ctgctgtgct cctaaaataa ttttcagcaa gtgccatttt acaccatctt 900 aggaagacat ctgagctgag cccaattctg tccccaccac ccaccctaca agcgacctga 960 cgcctgtggc cagaatgctg actcttcatt ccaggatatt tatgttttct aataataaaa 1020 gcaataacta ggccagaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaa 1073 44 2188 DNA Homo sapiens misc_feature Incyte ID No 3592659CB1 44 ggcgagtgtg tgtccttatc ctagcaattg gggcgcgggc ctgtgagcca gttggagttg 60 cggcggcggg aacgattggg ctgagcagag gacgacatgt tgcttttcgt ggagcaggta 120 gcatctaaag gaactggttt aaatcctaat gccaaagtat ggcaagaaat tgctcctgga 180 aatactgatg ccaccccagt aactcatgga actgaaagct cttggcatga aatagcagct 240 acatcaggtg ctcatcctga gggtaatgca gagctctcag aagatatatg taaagaatat 300 gaagtaatgt attcttcatc ttgtgaaacc acaagaaata ctacaggcat tgaagaatca 360 actgatggga tgattttagg accagaagat ctgagttacc aaatatatga tgtttccgga 420 gaaagcaatt cagcagtttc tacagaagac ctaaaagaat gtctgaagaa acaattagaa 480 ttctgttttt cacgagaaaa tttgtcaaag gatctttact tgatatctca aatggatagt 540 gatcagttca tcccaatttg gacagttgcc aacatggaag aaataaaaaa gttgactaca 600 gaccctgatc taattcttga agtgttaaga tcttctccca tggtacaagt tgatgagaag 660 ggtgagaaag tgagaccaag tcataagcgt tgtattgtaa ttcttagaga gattcctgaa 720 acaacaccaa tagaggaagt gaaaggtttg ttcaaaagtg aaaactgccc caaagtgata 780 agctgtgagt ttgcacacaa tagcaactgg tatatcactt tccagtcaga cacagatgca 840 caacaggctt ttaaatactt aagagaagaa gttaaaacat ttcagggcaa gccaattatg 900 gcaaggataa aagccatcaa tacatttttt gctaagaatg gttatcgatt aatggattct 960 agtatctata gtcaccccat tcaaactcaa gcacagtatg cctccccagt ctttatgcag 1020 cctgtatata atcctcacca acagtactcg gtctatagta ttgtgcctca gtcttggtct 1080 ccaaatccta caccttactt tgaaacacca ctggctccct ttcccaatgg tagttttgtg 1140 aatggcttta attcgccagg atcttataaa acaaatgctg ctgctatgaa tatgggtcga 1200 ccattccaaa aaaatcgtgt gaagcctcag tttaggtcat ctggtggttc agaacactca 1260 acagagggct ctgtatcctt gggggatgga cagttgaaca gatatagttc aagaaacttt 1320 ccagctgaac ggcataaccc cacagtaact gggcatcagg agcaaactta ccttcagaag 1380 gagacttcca ctttgcaggt ggaacagaat ggggactatg gtaggggcag gtaagaaaat 1440 aaagtacctg aaaacctttg ataataatgt gatcatcctg aataattgaa gaacgtgatc 1500 ttcataataa ttaaatgagc atttaattat tggtatatgg ttatattaaa taaatacgtt 1560 attttcagaa catgagttgg ttgcttttta taattattaa gaaatagagt gcccatacag 1620 aatatagctc tgaatcagag gtttataaag ttattctgaa gttccttata gctcatataa 1680 gaaagaatag cttagaaaat taacatatcc atttgcctta tggttttaat ttcttccagc 1740 ttttaaacta tagaagtggc tgggtgcggt ggctcacacc tgtaatccca acactttggg 1800 aggccgtggt gggaggatca tctcaggtca ggagttcaag accagcctgg ccaacatggt 1860 gaaaccctgt ctctatgaaa aaatacaaaa attagctggg catggtggca ggcgcctgta 1920 atcccagcta cttgggagcc tgaggtagga gaatcacttg aacccaggag gcagaggttg 1980 cagtgagcca aggttgcacc actgcattcc agcctgggtg acagagcgcg actctgtctc 2040 aaaatataaa taaactatag gggtgaggtt atatattgcc aacttgccta attaaacaat 2100 agtatggttc tggtttgaag ggatcactac taacaaatgg gctcatctta ctttatggtg 2160 tggtagtagg taaagttttt agtaaatt 2188 45 2265 DNA Homo sapiens misc_feature Incyte ID No 7596081CB1 45 cgggagccgg agcggagccg gggccggagc gggcggaatg gagcccctgc gcgcgcccgc 60 gctgcgccgc ctgctgccgc cgctgctgct cctgctgctg tcactgcccc cccgcgcccg 120 ggccaagtac gtgcggggca acctcagttc caaggaggac tgggtgttcc tgacaagatt 180 ttgtttcctc tcggattacg gccgactgga cttccgtttc cgctaccctg aggccaagtg 240 ctgtcagaac atcctcctct attttgatga cccatcccag tggccagccg tgtacaaggc 300 aggggacaag gactgcctgg ccaaggagtc agtgatccgg ccggagaaca accaggtcat 360 caacctcacc acccagtatg cctggtccgg ctgtcaggtg gtatcagagg agggaacccg 420 ctacctgagc tgctccagtg gccgcagctt ccgctcagtg cgtgaacggt ggtggtatat 480 tgcgctcagc aagtgtgggg gtgatggatt gcagctggag tatgagatgg tcctcaccaa 540 tggcaagtcc ttctggacac gacacttctc cgctgatgag tttgggatcc tggagacaga 600 tgtgaccttc ctcctcatct tcatcctcat cttcttcctc tcttgttact ttggatattt 660 gctgaaaggt cgtcagttgc tccacacaac ttataaaatg ttcatggccg cagcaggagt 720 agaggtcctg agcctcctat ttttctgcat ctactggggt caatatgcca ccgatggcat 780 tggcaacgag agtgtgaaga tcttggccaa gctgctcttc tcctccagct tcctcatctt 840 cctgctgatg cttatcctcc tggggaaggg attcacggtg acacggggcc gcatcagcca 900 cgcgggctcc gtgaagttgt ctgtctacat gaccctgtac acgctcaccc atgtggtgct 960 gctcatctac gaggcggaat tctttgaccc aggccaggta ctgtacacgt atgagtcgcc 1020 ggccggctac gggctcattg gactgcaggt ggcggcctac gtgtggttct gctatgctgt 1080 gcttgtctca ctgcgacact ttcctgagaa gcagcctttt tatgtgccct tctttgctgc 1140 ctataccctc tggttctttg cggttcctgt catggccctg attgccaatt tcggcatccc 1200 caagtgggcc cgggagaaga ttgtcaatgg catccagctg gggatccact tgtacgccca 1260 tggcgtgttt ctgatcatga cccgcccatc agcggccaac aagaacttcc cgtaccacgt 1320 gcgcacgtcg cagatcgctt cagccggagt ccctggaccc ggagggagcc aatccgctga 1380 caaggccttc ccgcagcacg tctatgggaa cgtgacgttt atcagcgact cggtgcccaa 1440 cttcacggag ctcttctcca tccccccgcc cgccacctcc gccgggaagc aggtggagga 1500 gacagcggtg gcggcggcgg tggccccgag gggccgcgtg gtgaccatgg ccgagccggg 1560 cgcagcctcc cccccacttc ccgctcggtt ccccaaggcg gccgactcgg gctgggacgg 1620 cccgacgccg ccctaccagc cgctcgtgcc ccagacggca gcgccgcaca ccggcttcac 1680 cgaatacttc agcatgcaca cggccggggg cactgcaccc ccggtctgag cacccctgcc 1740 cgcccctgcc ccatgggcca tgaccgggcc ccggccgggc tccggacccc tgctttatcc 1800 cggcccgaga gctcgcccat ccccggcctt cccgaccctt cccaccccgc gcgcccaggt 1860 tgggtacgct gcgtcccgcc cccctcccct ctgtgccaaa cggtcccgcg ggagccgctc 1920 tccccgtccc ctccctcagc ccctgccccg agcggcgccg gattctgggc tcccgctgtt 1980 ccgtgacctc cggccccctg gcccccttcg agacctctga ccccgctgga ctccggaaca 2040 cccgtggtga ccgccgggac cctgcctgtg actctccagg actctgcgac cccgggatgg 2100 atattgcgat gctggtctcg accctgaaac cctccctcgg atctgtgacc tcggacccgt 2160 actccatctg ccgcatctcc attccggggg ccttccctcg ggtccctggc agaaagacat 2220 tttacccctt cttgccaaaa taaaaaagga ttcgttttta tctct 2265 46 1600 DNA Homo sapiens misc_feature Incyte ID No 3009869CB1 46 agaacaccat cacctacttt gaagagcaat accatgctct ccctgctaca aaccagtaca 60 tccagttctg tgggtcttcc tcctgttcca ccaagctctt ctctttcctc tttgaagagt 120 aaacaggatg gtgacctcag gggtccagaa aaccccagaa acattcacac gtacccttct 180 acattagcct cctctgcatt atcttctcta tctcctccta ttaatcaaag agctacgttc 240 tcttcttcag agaaatgttt ccatccttcc ccagctcttt caagcctgat aaacagatct 300 aaaagagcat catcccaact atctggccag gagctgaatc cttcagctct tccttcactc 360 cctgtctcca gtgctgactt tgcctctctt cccaacttga ggtcctcctc tctccctcat 420 gccaatctgc ccaccctggt gccccagctc agtccctcag ctctgcaccc acattgcggc 480 agtggtacct tgccttcaag acttgggaaa tctgaaagca ccacccccaa ccacaggtca 540 cctgtttcaa ccccatcact tcccatatct ctaacaagga cagaggagct gatttcacct 600 tgtgcattgt ccatgtcaac aggcccagaa aataagaaat caaagcaata caagaccaag 660 tcaagctaca aggcttttgc agcaatccct acaaacacat tgcttttgga acagaaggca 720 ctagatgaac cagccaagac tgaaagtgtc tccaaggaca acacattaga accaccagtg 780 gagactccta caactcttcc aagagcagct ggtcgagaaa ccaaatatgc aaatctctcc 840 tcaccaactt ctacagtatc tgagagtcag ctgactaagc ctggagtaat tcgcccagta 900 cctgtaaaat ccagaatatt actgaaaaaa gaggaggaag tctatgaacc caaccctttc 960 agtaaatact tggaagataa cagcgacctc ttttctgaac aggatgtaac agtccctccc 1020 aagcctgtct cgctccatcc tttatatcag actaaactct atcctcctgc taagtcactg 1080 ctgcatccac agaccctctc acatgctgac tgtcttgccc caggaccctt cagtcatctg 1140 tccttctcct tgagtgatga acaggagaat tctcacaccc tcctcagtca caacgcatgc 1200 aacaagctga gtcatccaat ggtggctatt cctgaacatg aagctcttga ttccaaagag 1260 caatgaagtt ggagcagagg ctgaaaacac aggctgctga agttttttgg aatgctggtg 1320 ctaaccactt gctagattta actttttttt ttttttccag aatgagtgct ccctttatga 1380 gctgcagtgc agcagaacca aaaaaaaagt ttgctgcaat tatatagcat cacagtgctc 1440 tgctaacagc cagcatagaa gagatttacc tacagctttt tgcaccactg ttctagcctt 1500 taatgccttc tacttaatat taagctgacc gcaatactaa cgtgccccta tatttggcag 1560 ccaaataaag aagaatcgtg ggtaaataga aaaaaaaaaa 1600 47 4617 DNA Homo sapiens misc_feature Incyte ID No 7349094CB1 47 gggaagatgg cggccggcgg cggcggaggc agcagtaagg cctcctcctc gtcggcctct 60 tcggcagggg ctctggagtc ctcgttggat cgaaaattcc agtcggtaac caacaccatg 120 gagtccattc aaggcttgtc gtcttggtgt atagagaaca aaaaacacca cagtactatc 180 gtctatcatt ggatgaagtg gctccggaga tctgcatatc cccaccgttt gaatctcttt 240 taccttgcca atgatgtcat acagaactgt aaaaggaaaa atgcaatcat attccgtgaa 300 tcatttgctg atgtacttcc tgaagcagct gctctagtga aggatccatc tgtctctaag 360 tctgtagaac gaatctttaa aatctgggaa gatagaaatg tatacccaga agaaatgatt 420 gtggcattga gagaagcttt gagtaccact ttcaaaactc agaagcagct gaaagaaaat 480 ctgaacaaac aaccgaataa gcagtggaag aaatcacaaa catctacaaa tccaaaagct 540 gctctcaagt ctaagatagt tgctgaattt cgatctcagg ccctaattga agagctgttg 600 ctatacaagc gctcagaaga tcagatagaa ctgaaggaaa agcagttgtc aactatgagg 660 gtggatgtgt gcagcacaga aactctcaaa tgcttaaaag ataaaacagg tgggaagaag 720 ttctccaaag aatttgaaga ggcaagctcc aagctggaag aatttgtgaa tggattagat 780 aagcaggtga aaaacggacc ctcattaaca gaagcactgg aaaatgctgg aattttctat 840 gaagcacaat acaaagaagt aaaagtggtg gctaatgcat ataaaacctt tgctaaccga 900 gtaaacaatt taaagaagaa gttggatcaa ttgaagtcaa cccttccaga tcctgaagaa 960 tcaccagttc cttccccaag catggacgct ccctccccga ctggttctga gtctcctttt 1020 cagggaatgg gaggtgagga atcccagtca ccaaccatgg agagtgagaa atctgccaca 1080 cctgaacctg tgacagataa tcgtgatgtg gaagacatgg aactctcaga tgtggaagat 1140 gatgggtcaa aaatcattgt cgaggacagg aaggaaaaac ctgcagagaa gtcagctgta 1200 tccacttctg tacctacaaa gccaacagaa aatatctcaa aggcctcttc atgtacccca 1260 gtgcctgtga ccatgacagc aactccacct cttccaaagc ctgtgaatac ttctctttcc 1320 ccttccccag cattggcttt gccaaacctg gctaatgtgg atctggcaaa gatcagttcc 1380 atccttagca gtttaacatc agtcatgaaa aatactgggg tcagtcctgc atcaagacct 1440 tctccaggaa cgcccaccag ccccagcaac ctcaccagtg gcctgaaaac acctgcacct 1500 gccacgacaa catctcacaa ccctctggca aatatcctct ccaaggtgga gatcacccca 1560 gagagcattc tgtctgcact ttccaaaacc cagacacagt cagcccctgc actgcaaggc 1620 ctgtcatctt tacttcagag tgttactggg aacccagttc cagccagtga agctgcctca 1680 cagagcactt cagcctcccc tgccaacacc acagtctcta ccataaaggg aagaaatctg 1740 ccctccagtg cccaaccttt tattcccaaa agcttcaact attctcctaa ctcatcaact 1800 tctgaagtct cttcaacttc agccagcaag gcctcaattg ggcaaagccc agggctccca 1860 agcactactt ttaaactacc ttccaactct ttggggttta cagctaccca caatactagc 1920 cctgctgccc cacctactga agttaccatc tgccaatctt cagaggtctc caagccaaag 1980 ctggagtcag agtccacctc cccaagcctg gaaatgaaga ttcacaactt cttaaaaggt 2040 aatcctggtt tcagtggctt aaacttaaac atcccaatcc tgagcagttt ggggtccagc 2100 gccccatcag agagccatcc ctcagacttc cagcgtggcc ctactagcac ctcaatcgac 2160 aacattgatg gaacccctgt acgggatgaa cggagtggga cacccaccca ggatgagatg 2220 atggacaagc ccacatccag cagtgtagat actatgtccc tgctttctaa gatcattagc 2280 cctggttcct caacacccag cagtacaaga tcaccacccc ctgggagaga tgaaagctac 2340 ccccgagagc tctccaattc tgtatctaca tatcgaccct ttggtctggg cagtgaatct 2400 ccctataagc agccttctga tggaatggag agaccatctt ccctgatgga ctcttcacag 2460 gaaaagttct acccagatac ttctttccaa gaagatgagg attaccgaga ttttgagtat 2520 tcagggcctc caccctctgc catgatgaac ctagagaaga aaccagccaa atctatcctg 2580 aaatcaagca agctgtctga taccaccgag taccagccaa ttctgtccag ttatagccac 2640 agagcccaag aatttggggt aaagtctgcc ttccctccat ctgtaagggc cctcctggac 2700 tctagtgaga actgtgaccg tctctcatct tcccctgggc tatttggtgc cttcagcgta 2760 agagggaatg aacctgggtc tgaccggtca ccatcaccga gtaagaatga ttcatttttc 2820 acccctgact ccaaccacaa tagcttgtct caatctacca ctgggcatct cagtttgcca 2880 cagaagcagt acccagactc tcctcaccca gtcccacatc gttccctttt ctctccgcag 2940 aacacccttg ccgctcccac gggtcaccca cccacgtcag gcgtggagaa agtcctggcc 3000 tccaccattt ccaccacgtc gacgattgaa tttaagaata tgcttaaaaa cgcctcacgt 3060 aagccctcag atgataagca ttttggccag gctcccagca agggcactcc aagtgatggt 3120 gtcagtctct caaacctcac ccaacccagc ttgaccgcca ctgatcagca gcaacaagaa 3180 gagcactacc gcatagaaac ccgcgtctcc tcctcctgct tagacttgcc tgatagcaca 3240 gaagaaaagg gggcccctat agaaaccttg ggttatcaca gtgcatccaa taggaggatg 3300 tcaggggagc cgatccagac cgtagagtcc atccgagttc ctgggaaggg aaatagagga 3360 catgggcgtg aggcttcaag ggtgggttgg tttgatctga gcacatcagg tagctctttt 3420 gacaatggcc cttcaagtgc ctctgagttg gcatcccttg ggggtggggg cagcggaggc 3480 ctcactggct ttaaaacagc accatacaag gaacgggcac ctcaatttca ggagagtgtc 3540 ggcagctttc gttccaacag tttcaactca acatttgagc atcatcttcc cccatccccc 3600 ttggaacatg ggacaccctt ccagagagag ccagtggggc catcatctgc cccacctgtc 3660 cctcctaagg atcatggtgg tatcttctct cgagatgcac ccactcatct accctctgtg 3720 gatctttcga accccttcac aaaggaggca gccctggccc atgctgcccc accccctcct 3780 cctggagagc acagtggaat tcctttccct accccacctc ctcctccccc tcctggggaa 3840 catagcagca gtggtgggag tggtgtcccc ttttctactc caccccctcc tccaccccct 3900 gttgaccact ctggagttgt acccttccca gccccaccac tggcagagca cggagtggca 3960 ggggctgtgg cagtatttcc caaggaccat agttccctcc ttcaagggac cctggctgag 4020 cattttgggg tactcccagg acccagggac cacgggggcc ccacccaacg ggacctcaac 4080 ggccctggcc ttagccgtgt acgagagagc ctcaccctac cctcccattc tctggaacac 4140 ctgggcccac cccatggagg aggaggtggg ggaggcagca acagcagcag tggccccccc 4200 ttgggtccct cacacagaga caccatcagc cggagtggta taatcttacg gagtccccgg 4260 ccagactttc ggcctaggga accttttctc agcagagacc catttcacag tttaaagaga 4320 cccaggccac cttttgctag gggccctccg ttctttgcac caaaacgccc attcttccct 4380 cccaggtact gatggaaacc aagggaaagg cattttgaac agtctagaga acattggaag 4440 taggagtttg gtttattgtt gttgttttta tttgttttct ctttctcgat ttttttttta 4500 ttataacaaa gggcctctct tccaaagtaa gaaatcacat acgcttacgt tttactattc 4560 aattcaatcc tccctcccat ggcacttatc taccttcccc aagtggttgg tattaaa 4617 48 2622 DNA Homo sapiens misc_feature Incyte ID No 6826956CB1 48 tcggctgtgt ggtgcctgcg ctgggcaaga tggtgtgcgc tcgggcggcc ctcggtcccg 60 gcgcgctctg ggccgcggcc tggggcgtcc tgctgctcac agcccctgcg ggggcgcagc 120 gtggccggaa gaaggtcgtg cacgtgctgg agggtgagtc gggctcggta gtggtacaga 180 cagcgcctgg gcaggtggta agccaccgtg gtggcaccat cgtcttgccc tgccgctacc 240 actatgaggc agccgcccac ggtcacgacg gcgtccggct caagtggaca aaggtggtgg 300 acccgctggc cttcaccgac gtcttcgtgg cactaggccc ccagcaccgg gcattcggca 360 gctaccgtgg gcgggctgag ctgcagggcg acgggcctgg ggatgcctcc ctggtcctcc 420 gcaacgtcac gctgcaagac tacgggcgct atgagtgcga agtcaccaat gagctggaag 480 atgacgctgg catggtcaag ctggacctgg aaggcgtggt ctttccctac cacccccgtg 540 gaggccgata caagctgacc ttcgcggagg cgcagcgcgc gtgcgccgag caggacggca 600 tcctggcatc tgcagaacag ctgcacgcgg cctggcgcga cggcctggac tggtgcaacg 660 cgggctggtt gcgcgacggc tcagtgcaat accccgtgaa ccggccccgg gagccctgcg 720 gcggcctggg ggggaccggg agtgcagggg gcggcggtga tgccaacggg ggcctgcgca 780 actacgggta tcgccataac gccgaggaac gctacgacgc cttctgcttc acgtccaacc 840 tgccggggcg cgtgttcttc ctgaagccgc tgcgacctgt acccttctcc ggagctgcgc 900 gcgcgtgtgc tgcgcgtggc gcggccgtgg ccaaggtggg gcagctgttc gccgcgtgga 960 agctgcagct gctagaccgc tgcaccgggg gttggctggc cgatggcagt gcgcgctacc 1020 ccatcgtgaa cccgcgagcg cgctgcggag gccgcaggcc tggtgtgcgc agcctcggct 1080 tcccggacgc cacccgacgg ctcttcggcg tctactgcta ccgcgctcca ggagcaccgg 1140 acccggcacc tggcggctgg ggctggggct gggcgggcgg cggcggctgg gcagggggcg 1200 cgcgcgatcc tgctgcctgg acccctctgc acgtctaggc tgggagtagg cggacagcca 1260 gggcgcttga ccactggtct agagccctgt ggtcccctgg agcctggcca cgcccttgaa 1320 gccctggaca ctggccacat tccctgtggt cccttacaaa ctaactgtgc ccctggggtc 1380 cctgaagact ggctagtcct ggcagaacag tactttggag ttccctggag cctggccagc 1440 cctcacctct tctggataga ggattccccc aactccccaa ctttctccat gagggtcacg 1500 ccccctgagg acctcaggag gccagcagaa cccgcaggct cctgaagact ggccacgcct 1560 cctgagacca cttggaaaca gaccaactgc ccccgtggtc gcctggtggc tggacccccg 1620 ggattgacta gagaccggcc gtacaccttc tgcatctcac tggagactga acactagtcc 1680 cttgcggtca cgtgggacac tgggcgcctc ctcctccccc tcctcctcac ctggagagac 1740 tacaggaact tcagggtcac tccccgtggt cacatggagg ttgtgggccg aggcgcttat 1800 tttcccttat ggtgacctga gtcctggaga ctcccattct ccccctctcc ctgagagtcc 1860 cctgcagttt ctgggtaaca gggcacaccc ctctagtttc atgggcgagc acccccatct 1920 gccacctcag actgacacac agccagctgg ctcacttact gggggccacg tcccacccct 1980 cagatatttc tttgaaggga gagcaaaccc accctgtcct ctgacgtccc tttcccaact 2040 gtcaccaaac agaccatctt cccaggcctg gggaccggta agatccatgt cactagttat 2100 gcagagcagt tgccttgggt cccactgtca ccaaggcaac cagtcctgct gctacctgtc 2160 acctagagtc acacacccct tccctcatca ggcacaccca tgaagacagt gcctccctcc 2220 tccagctgta accatggata ccacacattt ctcatctcat tggcccccac cccagagacc 2280 tccacctcaa cttctggctg tccctaccct gactcaccgc catggagatc accctccccg 2340 aagctgtcgc cagggtgacc caacatccag ttctccggct ctcaccatgg aaacaaactg 2400 tccctgtccc caggcccact ccagttccag accaccctcc atgctccacc cccaggcggt 2460 ttggacccca ccactgttgc catggtgacc aaactctgga gtccgaggta acagaacacc 2520 tgtcccccta ggcttttcct tgtggacaac ggggccctgt tcaccaagct gttgccatag 2580 agactgtcaa cgttgtcctc catgacaacc agacttccag tt 2622 49 1636 DNA Homo sapiens misc_feature Incyte ID No 7486351CB1 49 atggacctga gcgccgccgc cgcgctgtgc ctttggctgc tgagcgcctg ccgcccccgc 60 gacgggctgg aagcggccgc cgtgctgcga gcggcggggg ctgggccggt ccggagccca 120 gggggcggcg gcggcggcgg cggcggcggg cggactcttg cccaggctgc gggcgccgcg 180 gctgtcccgg ccgccgcggt tccccgggcc cgcgccgcgc gccgcgccgc gggctccggc 240 ttcaggaacg gctcggtggt gccgcaccac ttcatgatgt cgctttaccg gagcctggcc 300 gggagggctc cggccggggc agccgctgtc tccgcctcgg gccatggtcg cgcggacacg 360 atcaccggct tcacagacca ggcgacccaa gacgaatcgg cagccgaaac aggccagagc 420 ttcctgttcg acgtgtccag ccttaacgac gcagacgagg tggtgggtgc cgagctgcgc 480 gtgctgcgcc ggggatctcc agagtcgggc ccaggcagct ggacttctcc gccgttgctg 540 ctgctgtcca cgtgcccggg cgccgcccga gcgccacgcc tgctgtactc gcgggcagct 600 gagcccctag tcggtcagcg ctgggaggcg ttcgacgtgg cggacgccat gaggcgccac 660 cgtcgtgaac cgcgcccccc ccgcgcgttc tgcctcttgc tgcgcgcagt ggcaggcccg 720 gtgccgagcc cgttggcact gcggcggctg ggcttcggct ggccgggcgg agggggctct 780 gcggcagagg agcgcgcggt gctagtcgtc tcctcccgca cgcagaggaa agagagctta 840 ttccgggaga tccgcgccca ggcccgcgcg ctcggggccg ctctggcctc agagccgctg 900 cccgacccag gaaccggcac cgcgtcgcca agggcagtca ttggcggccg cagacggagg 960 aggacggcgt tggccgggac gcggacagcg cagggcagcg gcgggggcgc gggccggggc 1020 cacgggcgca ggggccggag ccgctgcagc cgcaagccgt tgcacgtgga cttcaaggag 1080 ctcggctggg acgactggat catcgcgccg ctggactacg aggcgtacca ctgcgagggc 1140 ctttgcgact tccctttgcg ttcgcacctc gagcccacca accatgccat cattcagacg 1200 ctgctcaact ccatggcacc agacgcggcg ccggcctcct gctgtgtgcc agcgcgcctc 1260 agccccatca gcatcctcta catcgacgcc gccaacaatg ttgtctacaa gcaatacgag 1320 gacatggtgg tggaggcctg cggctgcagg tagcgcgcgg gccggggagg gggcagccac 1380 gcggccgagg atccccagct ggtgagcagc agcgggccac cctgtcaccg agcgtgggtg 1440 catgtccgat gtgacccagc gccctctcag aggagggaga gcacacgttc acactcacac 1500 acactcgtgc agtcacgcac acatttaccg gggacagcat gtgaaagcct tgggaagaga 1560 tgacctgccg gtaccgaatg tcaaagccct gtgtattttg caaacagata accatggcgc 1620 ccactgcccc caaaaa 1636 50 943 DNA Homo sapiens misc_feature Incyte ID No 1709023CB1 50 gaaaaagatc aggaaattaa gtggcagaac atcttcacgg gagctcagtg ataaggatca 60 tgccctccac gatggtgaaa tgaaagtatt tgatgtcggc ctggtgtgtg gaattgtggg 120 cccacacatt tctcttcctc tctcagatcc tggtgtatag cctggaagca ggacgccgcc 180 tcttgaagct gggtaacgtt ctccgtgact tcacgtgtgt caacctcagc gacagccctc 240 ccaacctcat ggtcagtggc aacatggacg ggagggtgag gatccacgac ctccgcagtg 300 gtaacatcgc cctgtcgctc tccgcccatc agctcagggt ctctgctgtg cagatggatg 360 actggaagat cgtcagtgga ggcgaggaag gcctggtgtc cgtgtgggat tatcggatga 420 accagaagct gtgggaggtg tattccgggc acccggtgca gcacatctca ttcagcagcc 480 acagcctcat cacggccaac gtgccttacc agacggtaat gcgaaacgcc gacctggaca 540 gcttcactac tcacaggaga caccgggggc tgatccgcgc ctacgagttt gcggtggacc 600 agctggcctt ccagagccct ctccctgtct gccgttcatc ctgtgacgcc atggccactc 660 actactacga cctcgcactg gcctttccct ataaccatgt ttagggatgt gcctcagttg 720 ggagcaagga gaaaaatggg aagaaccagt tttatccatc ttaaaacgcc aggcacctct 780 tcacaggtgg taaacattta ggggaagaaa gcagcccagg gtgccatgcc tgacagcacg 840 catctccctg acccctgcac ttcccccagc gcctggggca agctggcgtg tgccagggct 900 cgagtcccac gtgctgccaa ctcaaacata gcctccttcc cca 943 51 827 DNA Homo sapiens misc_feature Incyte ID No 1556012CB1 51 cgtcagtcta gaaggataag agaaagaaag ttaagcaact acaggaaatg gctttgggag 60 ttccaatatc agtctatctt ttattcaacg caatgacagc actgaccgaa gaggcagccg 120 tgactgtaac acctccaatc acagcccagc aagctgacaa catagaagga cccatagcct 180 tgaagttctc acacctttgc ctggaagatc ataacagtta ctgcatcaac ggtgcttgtg 240 cattccacca tgagctagag aaagccatct gcaggtgttt tactggttat actggagaaa 300 ggtgtgagca cttgacttta acttcatatg ctgtggattc ttatgaaaaa tacattgcaa 360 ttgggattgg tgttggatta ctattaagtg gttttcttgt tattttttac tgctatataa 420 gaaagaggta tgaaaaagac aaaatatgaa gtcacttcat atgcaatcgt ttgacaaata 480 gttattcagg ccctataatg tgtcaggcac tgacatgtaa aattttttta attaaaaaag 540 agctgtaatc tggcaaaaag tttctatgta atatttttca tgccttttct cataaaccca 600 gacgagtggt aaaaatttgc cttcagttgt aataggagag ttcaaacgta cagtctccct 660 tcaacctatc tctgtctgcc catatcaaaa ttataaatga ggaggacagc aggccccaag 720 aaagtaggga ctaagtatgt cttgttcaaa attgtatatt cagtgactta cactatgcct 780 agcacacaac acacactgag taaatatttg ttgagtgaaa taaaatg 827 52 988 DNA Homo sapiens misc_feature Incyte ID No 1838010CB1 52 gtcagagcaa aacctcctct atctgcacat cctggggacg aaccgggcag ccggagagct 60 gcggccggcc cagtcccgct ccgcctttga agggtaaaac ccaaggcggg gccttggttc 120 tggcagaagg gacgctatga ccgcagaatt cctctccctg ctttgcctcg ggctgtgtct 180 gggctacgaa gatgagaaaa agaatgagaa accgcccaag ccctccctcc acgcctggcc 240 cagctcggtg gttgaagccg agagcaatgt gaccctgaag tgtcaggctc attcccagaa 300 tgtgacattt gtgctgcgca aggtgaacga ctctgggtac aagcaggaac agagctcggc 360 agaaaacgaa gctgaattcc ccttcacgga cctgaagcct aaggatgctg ggaggtactt 420 ttgtgcctac aagacaacag cctcccatga gtggtcagaa agcagtgaac acttgcagct 480 ggtggtcaca gataaacacg atgaacttga agctccctca atgaaaacag acaccagaac 540 catctttgtc gccatcttca gctgcatctc catccttctc ctcttcctct cagtcttcat 600 catctacaga tgcagccagc acagtgagct cagagaacgc aaagggagag agggggagtg 660 aaggattttc tcgaaccagc cattccaaac ttccggagca ggaggctgcc gaggcagatt 720 tatccaatat ggaaagggta tctctctcga cggcagaccc ccaaggagtg acctatgctg 780 agctaagcac cagcgccctg tctgaggcag cttcagacac cacccaggag cccccaggat 840 ctcatgaata tgcggcactg aaagtgtagc aagaagacag ccctggccac taaaggaggg 900 gggatcgtgc tggccaaggt tatcggaaat ctggagatgc agatactgtg tttccttgct 960 cttcgtccat atcaataaaa ttaagttc 988 53 783 DNA Homo sapiens misc_feature Incyte ID No 1741076CB1 53 tgcacccgac ccccagaaag tgtcttttga gggtaacttg tttcttcttt tcctgaacct 60 gtggcatatg tcacaactct tagcagctgt cccagcactg gttcttttcc ctcctggcag 120 tgaccagagc tgtcattaag tgactcattg tgagagcaga gactgtctct gtcaccactg 180 ttgaatgaat gaatgcatgc atggatgaat gaatgaatga aacatgaaac tctttcctga 240 gttctgtcct ttcattgctc tagcatgctg ccctctgagc acttcccacc cctcgagggg 300 ggtcatccgt ataggggtgg gaacagagcc aaggtgccta atggggtccg aagcctctcc 360 acctggtgaa attgcctgta gattccatgt ctgtgtctgt ccacttgacc catgctccag 420 gccccgctgc cctcatctct cgttcccctg atgaatcaca cgaggcctgg tgacacagca 480 tcatcactct ccttatccag cagacgcgac atcaccctcc ttcacccgct gcaaactggc 540 tgcccaggca ttacaggaag ccaccctgcc ccctcctggg cctggctgcc ctcgcctctg 600 taatatcctt tttctaatag agtgacctga accctatgtg ctgttctaaa agcagcctca 660 gaagcccctg agacaggcag ccaggtaatt cccctggcgg aggcacgatc ttaccttgcc 720 ctgcatgtct gaacctgctg gctggctgaa gaatgtccgt tttatagaat ataataaaat 780 gag 783 54 2974 DNA Homo sapiens misc_feature Incyte ID No 2692031CB1 54 ggctcgcgcc gcgggtaggc tccctcagat ccccgtagat ctcagtagat ccggcgtgta 60 ttccccaccc gcggagtatc ccggtgtgca gcgatctccc gagagttggc gcagggccac 120 ttggctgcag agaacgtgtg caccttcagt ccgggaaacc cgccccagcc gagtagccgc 180 gcatcctggg aagcctggcg agccacggcg ccgggggcgg ccaaggggag gcgggatgag 240 tctgcgagcc ggctgagcgc gccgaggagc cggccggggc accgccgggg acatggcgtc 300 ttggctccgg agaaagctgc gtggcaagag gcggccagtg atagcgttct gcctcttgat 360 gatcctatct gcgatggctg tcacccgctt tcccccacag cgtccatccg ccggcccaga 420 ccctggtccc atggagcctc agggggtaac tggcgcccct gcaacccata tccggcaggc 480 tttgagctcc agccggaggc agcgggcaag aaacatgggc ttctggagaa gccgtgcttt 540 gcccaggaac tccatcttgg tctgtgctga ggagcaaggc catagagcaa gagtggacag 600 aagcagggag tccccaggag gggacctcag gcatccaggg agggtgagga gggacattac 660 tttgtcagga catccaagac tcagtactca gcatgttgtg ctcctgaggg aggatgaggt 720 tggagatcca ggaaccaaag acctgggcca cccccagcat ggcagtccca tccaggagac 780 acagagtgag gtggtcaccc tggtcagtcc actcccaggg agtgacatgg cagctttacc 840 ggcttggaga gctacttctg ggctgacact ctggccccat acagcagaag gcagggatct 900 gctgggagct gagaacagag ccttgactgg tgggcaacaa gcagaggatc ccaccttggc 960 ctcaggagct catcagtggc ctggctctgt tgagaagctg caagggtcag tatggtgtga 1020 tgctgagacg ctgttgagca gctcgaggac tggtgggcag gctcccccat ggctgacaga 1080 ccacgatgtg cagatgctcc gtctgttggc acagggggag gtggtggaca aagccagggt 1140 ccccgcccat gggcaggtgc tacaggttgg cttctccact gaggctgccc ttcaggacct 1200 gtcctctccc aggctcagcc aactctgttc ccaagggctc tgtggcctga tcaagaggcc 1260 tggggacctg cctgaggtcc tgtccttcca cgtagatcgt gtgctggggc tgcgccggag 1320 cctacctgct gtggcccgcc gcttccatag ccccctcctg ccctaccgat acacagacgg 1380 tggagcaagg cctgtcatct ggtgggcgcc cgatgtgcag cacctgagcg acccagatga 1440 ggatcagaac tctctggcct tgggctggct gcagtatcag gccctgctgg cacacagctg 1500 caactggcca ggccaggccc cgtgcccggg catccaccat accgagtggg cacgcctggc 1560 gctcttcgac ttcctgttgc aggtccacga ccgcttggat cgctactgct gtggcttcga 1620 gcctgagccc tcagacccct gtgtggaaga gaggctccga gagaaatgcc agaacccagc 1680 cgagctgcgg ctggtccaca tcctggtccg gagcagcgat ccatctcacc tggtctacat 1740 cgataacgct ggcaaccttc agcaccctga ggacaagctg aactttcggc tgctggaggg 1800 catagatggg tttcctgagt ctgccgtgaa ggttctcgca tcagggtgtc tacagaacat 1860 gctgctgaag tcgctgcaga tggacccagt gttctgggaa agccaaagcg gagcccaggg 1920 gctgaagcag gtcctccaga ccctggagca gcgaggacag gtgctgctgg gacacatcca 1980 aaagcacaac ctcacactct tcagggacga ggacccataa gccgcacaca gccctgagtc 2040 aatgagcatc catcctgatg gccacatttt cttgggctca ctcatcttga ggacaaatgg 2100 gaaaagccag aagccagagg ggcacaagga tgtcacggga tatttcacct gcctgggatg 2160 gtggaggtag tatggggttt tcaatctcaa agcgtccctt tctgccttct cggctctggc 2220 tatttattcc cttgcaccaa caaatacatt cgaaaatgtt ctgtgagctg ctcaagaaac 2280 tgtaaaaatg tgtgatgcac gtgcatatgc agagtgggag aactttgtgt gtgtgtagag 2340 gtgtgtaggt gtgggtggca tgtgtgcacg cctgcatgca atacctgaga ccaacctaat 2400 aaaggtacaa tcttcataga actgcacttg cagcctggag ttgctctggc tgaaagtaga 2460 ctcaggctta agaaatgaaa cataatgcgt ttgtctttat agactttaaa ttttcaatta 2520 ttactcagtt atgtttttgg tttaaaaaat tataaaagtc taaaagtaat acatgctcag 2580 taaaaacaag tccataaaaa atagaagcat atgacaaaaa gcataagtcc cacaaactcc 2640 ctagcggtgt gtatgtgtgt gtgtgttatt catggtcaca ctacatgcaa attaaaaaat 2700 gaaagtgtgg tcatgctttg tcaactcact atatttttac tttattaact atattctgta 2760 tcagccatct gaattgaccc aatctttatt ggtgactgca tgaaattcca aggcagggat 2820 gtgtcatatt ttctttagct ggtcccataa tcatgaacat ttaagtagct ccaatttttc 2880 atcaattaca gacattgccg ccatgaacat gattgcatgg cgtgcaagta tttctgcgag 2940 gtagatttcc gtacgggatt tctggggcaa aggg 2974 55 1939 DNA Homo sapiens misc_feature Incyte ID No 7237245CB1 55 aacgatctga ccgccttggc ctcccaaaat gttgggattt gtgagccacc accgggccta 60 accctaccaa cttaaaatag aaacatctca agctacctta acttatttta caggaaaaaa 120 atggattact tttcaggcta attttgtgac atttctagat attatctaat agttaggccc 180 tttgcacagt gtaggccaat ggcaggtaaa catttgttag caggagactc atttggtgaa 240 ataaaattct cagccggcgc ggtggctcac gcctataatc tcaacacttt gggaggccgt 300 tgcgggcgga tcacctgata tcaggaattg acaccagcct ggccaacatg gcaaaacccc 360 atctctacta aaaatataaa aaattagcta ggtgtggtgg cacgtgcctg tggcactgag 420 gaggctgagg cacaagaatc gcttgaatcc aggaagcaga ggttgcggtg agccgaaaat 480 gcaccactgc actccagcat gggcaacaca gtgagactgt tgtctcaaaa aaaataaatg 540 aataggccgc gctcccgccc agggaggatg cgccgacgcc ccgagcgccc ggccctccgc 600 agcagcccgg cagactgcct ctgtcatcag gaccctccgt ccacgtcccc tgtgcggcca 660 gcgtcagagc catggcgatg gaggagagga agcccgagac cgaggcaacg agagcacagc 720 cgaccccttc gtcatccacc actcagagca agcctacgcc cgtgaagcca aactatgctc 780 tcctaaagtt cacccttgct ggccacacca aagcagtgtc ctccgtgaaa ttcagcccga 840 atggagagtg gctggcaagt tcatctgctg ataaactcat taaaatttgg ggggactcat 900 atgatgggaa atttgagaaa accgtctggt cacagcctgg ttcgtcagat tctaaccttt 960 ttgtttccgc ctcagatgac aaaaccttga agatacggga cgtgagctcg ggaaagtgtc 1020 tgaaaaccct gaagggacac agtaattatg tcttttgctg taacttcaat ccccagtcca 1080 gccttactgt ctcaggatcc tttgatgaaa gtgtgaggat atgggttgtg aaaacaggga 1140 agtgccacaa gactgctgct cactccgatc cagtctcggc cattcatttt aatcgtgatg 1200 gattcttgat agtttcaagt agctatgatg gtctctgtca catctgggac accgcctcag 1260 gccagtgcct gaaaacgctc actgatgatg acaacccctg gtgtcttttc gtgaagctct 1320 ccccgaaggg tggatacatc gtggctgcca cgctgggcaa cactcaagct ctgggactaa 1380 gcaaggggaa gtgcctgaag acatacactg gccacaagaa cgagaaatac tgcatatttg 1440 ctaatttctc tgttactggc gggaagtgga ttgtgtctgg ctcggaggat aaccttcttt 1500 acatctggaa ccttcagacg aaagagattg tacagaaatt agaaggccac acagatgttg 1560 tgacctcaac agcttgtcac ccaacagaaa acatcatcac ctctgctgcg ctagaaaatg 1620 acaaaacaat taaactgtgg aagagtgact gttaagtccc tttgctccca catgcgatag 1680 accgtcagga agttgacccg gattggcaag aaacatgatg tctcggaggc ggtcccctgg 1740 gtctgtgcct gggggtcagg actgggcctg atttgagcct cctttttgaa gatgatttgg 1800 ccgagtgtgg accaccggaa agttctaaag ttgctggtga catttcttgc caattctcta 1860 acactgtcta gggaagagtt cctagtctgt tgtgttcaaa cagagtcaac aaaaattttt 1920 aattttttgt tacaaaagg 1939 56 815 DNA Homo sapiens misc_feature Incyte ID No 7488021CB1 56 gtgcaatggc tagtactatg tgtcaacttg tctaggctat actgctcagc tgtgtggtca 60 aacagtagtc tagatgttgc tgtgaaggta ttttgtagat gtgatcaaca tttacaatca 120 gttgatttta agtaaagcag tttaacttcc ataatgtgga tgggcctcat ccaattagtt 180 gaaggtgtta agagaaaaga ccaaggtttc ctggaaaagg aattctacca caagactaac 240 ataaaaatgc gctgtgagtt tctagcctgc tggcctgcct tcactgtcct gggggaggct 300 tggagagacc aggtggactg gagtagactg ttgagagacg ctggtctggt gaagatgtcc 360 aggaaaccac gagcctccag cccattgtcc aacaaccacc caccaacacc aaagaggcga 420 ggaagtggaa ggttcccaag acaacccgga agggaaaagg gacccatcaa ggaagttcca 480 ggaacaaaag gctctcccta aaagaccgcc gcttcaaaaa aacctgagga atggagtggg 540 ccaacactat ccagccactc tgaccagccg aacgaggaac tcaatcaaaa tgagccatag 600 cgggaccaca agggcaagga gaccaccacc ttctccagtc tctcttcgga cagccagtaa 660 ttcccgggca aggccagaga cttcaagtct atctgaaaag tctccagagg tctaacccca 720 gataaatagc caacagggtg tagagtacat tttacacccc aaagagtgtg ccccatggtg 780 atgaaaataa agtgaacatg ttgcaaaatg aaaaa 815 57 1278 DNA Homo sapiens misc_feature Incyte ID No 7390973CB1 57 ggcctctgga gctcagctgc cagtccacgt ctagggaatc ttagcatctg ggaccaagac 60 actttacagc aatcatcacc ctttgcagag gaggtgagct caccaggact catctgccat 120 ttcagacctt ttgctgctac ctgccaggtg gcccccactg ctgacgagag atggtggacc 180 tctcagtctc cccagactcc ttgaagccag tatcgctgac cagcagtctt gtcttcctca 240 tgcacctcct cctccttcag cctggggagc cgagctcaga ggtcaaggtg ctaggccctg 300 agtatcccat cctggccctc gtcggggagg aggtggagtt cccgtgccac ctatggccac 360 agctggatgc ccagcaaatg gagatccgct ggttccggag tcagaccttc aatgtggtac 420 acctgtacca ggagcagcag gagctccctg gcaggcagat gccggcgttc cggaacagga 480 ccaagttggt caaggacgac atcgcctatg gcagcgtggt cctgcagctt cacagcatca 540 tcccctctga caagggcaca tatggctgcc gcttccactc cgacaacttc tctggcgaag 600 ctctctggga actggaggta gcagggctgg gctcagaccc tcacctctcc cttgagggct 660 tcaaggaagg aggcattcag ctgaggctca gatccagtgg ctggtacccc aagcctaagg 720 ttcagtggag agaccaccag ggacagtgcc tgcctccaga gtttgaagcc atcgtctggg 780 atgcccagga cctgttcagt ctggaaacat ctgtggttgt ccgagcggga gccctcagca 840 atgtgtccgt ctccatccag aatctcctct tgagccagaa gaaagagttg gtggtccaga 900 tagcagacgt gttcgtaccc ggagcctctg cgtggaagag cgcgttcgtc gcgaccctgc 960 cgctgctgtt ggtcctcgcg gcgctggcgc tgggcgtcct ccggaagcag cggagaagcc 1020 gagaaaagct gaggaagcag gcggagaaga gacaagagaa actcactgca gagctggaaa 1080 agcttcagac agagcttggt aagtgacccc tcttagaact atttctcctc agggccgggt 1140 ccagtggctc acacctgtaa tcccagtact ttgggaggcc gaggcgggtg gatcacgagg 1200 tcaggagatc gagaccagcc tggctaacac agtgaaaccc cgtctcttct aaaaatacaa 1260 aaaattagcc cggcgtgg 1278 58 901 DNA Homo sapiens misc_feature Incyte ID No 4890777CB1 58 catcctccgt ggtagctggg attacaggtg cgtgccgcca cgtctggcta atttttgtat 60 ttttggtaga gacagggttt caccatgttg gccagactgg tctcgaatgc ctgacctcag 120 gtgatctacc cacctcagcc ccctaaagtg ccagaattac aggtgtgagc catggcaccc 180 agctgctgca atgattttta aaattgtttc tgcttgcccc ctactgccac ctctcatctg 240 cacatacctt cacccaacat gttcagcagc agcactgata caaactggtg tggaaaatgg 300 actacaggac ctgatgatat tcccaggctc actctgctca caggcccctt ctgagaaagg 360 cagctgggga tgcttccttt catcaccccc aagcttgact ggtgcaatca gtaggctcag 420 ctggaagagc tcagatgctc cctgggttgg acaagggaca aagagatcca gtcagatttc 480 ccctcttctc ctttacagaa ttcgaatatg aaatatatag cgtaagggat acaggtggcg 540 tcaccaaaca tcccagttca cctatgactt tgggtgtggc ctggtgctga aactggaaaa 600 gtcccaggaa aactgggttg agtttggtca ccccagatgc aggcagtatg gcaggcgaaa 660 gctgaggttg cacaaagaca gcaagcatag ccaggtggtg cagtggcaca gtggctcagt 720 ggcatggtgg cttggtgact cttgtctgta gtcttagcta catgggaggc tgaggtggga 780 ggatcacttc agcccagaag tttgaggcca gcccaggcaa cacagcgaga cctcatcttt 840 acaaaaatat tttcagaaat tagccggaag cccgggagtt tgagagtgca gtgagctgat 900 a 901 59 976 DNA Homo sapiens misc_feature Incyte ID No 5511444CB1 59 ctaggcaaag cgttgagata gatgtgcctt tctctgtcca gctcaggcta gactggcctg 60 cccctctctt cacaagttcc ccaaaggggc atgggagttg aggatggagg atagaaccta 120 gagtcccaac ggagccagac atgagagagg gagtgagaga aaggcctact caggctattg 180 tgttcatgcc tcgtgccaca tatgcctgtt cccttctgtc tctgggcctg ttctcagtgc 240 cctccgtctc cacttgctca aatctggccc ttcctgccat acccagctgc agtcatcttc 300 tagaaagctt ccccctgctg cttctggaaa tcagcagagg gtgggcaagg gggaagtcag 360 taacctccaa gctccctgcc aactctgaga ttctccagga gtttgatgag catcaggggt 420 tgggggcatg gaaggctggt ggcccaggcc atcgatgcct tagtagcctc acaggaagga 480 agcagatggc acagccagcc agctgagtag gcccacattt ggcttcagga ggctttgccc 540 agagccctgt gcagcaggca cctgccaaac agcccccaga ggggtgctat ttgagccctg 600 ggtctttggc tgctggaggc agctacttgt tgggaagttc ccagaagctc ctgcccacac 660 ctgctccccc tgtctgccct ccaaggtttg tttacagttc ggcctttgac aggctgaagt 720 ctgagatcta agaggagaga gagatctggg tggccgggga ccctcttctg gcttagcatt 780 ctgtgccagg gctctgcagc ccagcttggc ctcggagaga tgtgttcact gaggggaaga 840 attcaggcct gctgatcttt tccctgccaa ctccactttt cccatcatga ccattccctc 900 caccttctgg aattctctcc acttcctact ttcttttttt ttgatctcct ctttcacaca 960 cacacacacg cgcgtt 976 60 2054 DNA Homo sapiens misc_feature Incyte ID No 6104370CB1 60 ccgctgctca atgctgggga cagacgtcag gggactgtgg acgtcatcgg ccgagtgact 60 atttccttat gaccagcctc tctccgagct gattttcctg ttctgtgctc tctcagccaa 120 gctgtttgag gttggctcag gaaactaggc caacaatgga attcaaagac aatcccacca 180 aagagaaaac cagcagggtg ggcgacgcct gggctccaag aaccggtggg gagctccatt 240 tccctcagat ggagcgtttc ctaaccccgg ggcaactttc ccgaaacatg gcaggcttgc 300 ctgacccaaa tagcccctta ttcttggctg cacttgtgac caccgggccg agctcctcgg 360 aggcgtggac aaaggaggcc ttggcgagaa cagggttcgg tggccagtgg gtggagaagt 420 cggtgctggc tgcgccgtgg agcccgtgga tcaacatttg ctgaggacct cagtgcggaa 480 agtcgtggtc gcacttcctt ccgggtctgc tgagctgcca ctcacggcgg gagagttggg 540 acgtcctgga attctggaaa gcctcctgct ctgaaggagt tcaaggtttt cctgtccggt 600 ctgacatccc cagacatttg ccctgctagg gctggagaaa ggtgtccagg catgtgaagg 660 aacaatttga gggacaatct ggcttttttt ttttttaaca gttcttttct aaacacctca 720 gaatgaatga aacaaagtcc tatttatcac tagagatgaa gacacatccc tgatttacgt 780 tgccacgtgg ggagaagtgc tttgtttcta ctcagcagaa ggagacaggg gcaggcggga 840 ggagctgtct caggaacacc agcctgggtt tcccaccctc cctgctgtgg ctctcagctg 900 atccgaggct ggctcaggag aggagggaag catgcctgag actgctctgt ctttctgctc 960 cagcaacaga gagccaaaga aaagacacga ggcccaaagt atcaccttct aaatcacctc 1020 cctcagctac tcccccagga tttccaaata cccaggttcc cctcgggagc tgcctggagc 1080 tgcctctgcc gcccgctcct ctaggcgtcc atgatgagcc cagggcttcc ccctcaggaa 1140 ccaaaccgaa ctgactgtct tggttttctc cttgttctcc acgaatcctc tgcacatttt 1200 aaccttccag gcagcagcta tgaatccgtt cccagagcca ggctagacaa tacaacaccc 1260 atttcccagc tgcttgcagc tcttgcatta gctgggaagc agctttacct taagggaatt 1320 taccaccctt agaatttttt tttttttaga aaaatataca ttttttcttt ccttttaaaa 1380 aagccttcag gctcttgcta acttcacaac tggagcccta tcagaaaaag gcaagttgtc 1440 aaatggcaaa tatgaagtcc gtgttgttga atcgtgagcg ccgggggaga atagaggggg 1500 ctgtggagct gtctcggggt cagagccctg cggagacgcc agggctgggc gggcctgaga 1560 cctccgcctg cagtcagcaa ggcccccttg gctgatggac ctgagaattt ctgtgttact 1620 tctttttatt tctgcatgct tcacgtcaca gaattttcga aaagtggcaa tagaaccaaa 1680 tgataaaagc aattctagga tagagcgtct tgctttcata tgaacagcat tccatctaag 1740 acggttcaac acttcctaat tcctgtccac catcttcagg gttccttgga gtggtggccc 1800 cctggtgacc agctggcaca gtgatttgat catgtcctca cagctccctc cgaggccttt 1860 ttcttgcgtg aagcatgaag ggcgactttg cggttggagc ctggtcccgc ttcttcccat 1920 gagtgttttg ttttccctcc ctctgacgct cacatgtcca tgctggctgg tggcttcttg 1980 atgctgcaag cttagtgaac acacaggaat cctgctccta gggccagcac accctccgtg 2040 gctccttcct tggc 2054 61 610 DNA Homo sapiens misc_feature Incyte ID No 7488468CB1 61 atgcctctga gaaagctgtc tttccatggt ggatcccgct ggatgcccgt gaacacgggg 60 ccagcttgca gagagctgga aggaggcctc ctggcggcac ccaggcctga cacagatttc 120 atttctgatt gcggaatttt actctcaaac caaaagatgc tacatgccgc tcctgacgcc 180 gtggcacgga atcacgccgc gtgtcccttg tttccggatt tctcttctgt ggcttattga 240 tggcactcaa gcaccgcaca gcaatgacgt ctgtcctggc agggcacacg cactctgcgt 300 ctgaatgagt attgagctaa ttccaaagcc cagcagagac gtgggcgcgc gtttatctgt 360 aggagaccag gcgcgccatg gttggctctg gccgcgggac cctgggctga gcaccgaccc 420 aggccacccc aagtcaccaa aagagggtag ggaggggtgg acaaaagtat ttattttgcc 480 tattttcttg ccagtgtcca gattcaaatg tactgttttt aaactacatt agcactttct 540 gccctgtggc ctgcaatgat tgtgctgtga ttattcaaca ccataaataa taatgcagca 600 tttcaccaaa 610 62 2852 DNA Homo sapiens misc_feature Incyte ID No 7503555CB1 62 ggctcgcggc cgcgggtagg ctccctcaga tccccgtaga tctcagtaga tccggcgtgt 60 attccccacc cgcggagtat cccggtgtgc agcgatctcc cgagagttgg cgcagggcca 120 cttggctgca gagaacgtgt gcaccttcag tccgggaaac ccgccccagc cgagtagccg 180 cgcatcctgg gaagcctggc gagccacggc gccgggggcg gccaagggga ggcgggatga 240 gtctgcgagc cggctgagcg cgccgaggag ccggccgggg caccgccggg gacatggcgt 300 cttggctccg gagaaagctg cgtggcaaga ggcggccagt gatagcgttc tgcctcttga 360 tgatcctatc tgcgatggct gtcacccgct ttcccccaca gcgtccatcc gccggcccag 420 accctggtcc catggagcct cagggggtaa ctggcgcccc tgcaacccat atccggcagg 480 ctttgagctc cagccggagg cagcgggcaa gaaacatggg cttctggaga agccgtgctt 540 tgcccaggaa ctccatcttg gtctgtgctg aggagcaagg ccatagagca agagtggaca 600 gaagcaggga gtccccagga ggggacctca ggcatccagg gagggtgagg agggacatta 660 ctttgtcagg acatccaaga ctcagtactc agcatgttgt gctcctgagg gaggatgagg 720 ttggagatcc aggaaccaaa gacctgggcc acccccagca tggcagtccc atccaggaga 780 cacagagtga ggtggtcacc ctggtcagtc cactcccagg gagtgacatg gcagctttac 840 cggcttggag agctacttct gggctgacac tctggcccca tacagcagaa ggcagggatc 900 tgctgggagc tgagaacaga gccttgactg gtgggcaaca agcagaggat cccaccttgg 960 cctcaggggc tcatcagtgg cctggctctg ttgagaagct gcaagggtca gtatggtgtg 1020 atgctgagac gctgttgagc agctcgagga ctggtgggca ggctccccca tggctgacag 1080 accacgatgt gcagatgctc cgtctgttgg cacaggggga ggtggtggac aaagccaggg 1140 tccccgccca tgggcaggtg ctacaggttg gcttctccac tgaggctgcc cttcaggacc 1200 tgtcctctcc caggctcagc caactctgtt cccaagggct ctgtggcctg atcaagaggc 1260 ctggggacct gcctgaggtc ctgtccttcc acgtagatcg tgtgctgggg ctgcgccgga 1320 gcctacctgc tgtggcccgc cgcttccata gccccctcct gccctaccga tacacagacg 1380 gtggagcaag gcctgtcatc tggtgggcgc ccgatgtgca gcacctgagc gacccagatg 1440 aggatcagaa ctctctggcc ttgggctggc tgcagtatca ggccctgctg gcacacagct 1500 gcaactggcc aggccaggcc ccgtgcccgg gcatccacca taccgagtgg gcacgcctgg 1560 cgctcttcga cttcctgttg caggtccgga gcagcgatcc atctcacctg gtctacatcg 1620 ataacgctgg caaccttcag caccctgagg acaagctgaa ctttcggctg ctggagggca 1680 tagatgggtt tcctgagtct gccgtgaagg ttctcgcatc agggtgtcta cagaacatgc 1740 tgctgaagtc gctgcagatg gacccagtgt tctgggaaag ccaaagcgga gcccaggggc 1800 tgaagcaggt cctccagacc ctggagcagc gaggacaggt gctgctggga cacatccaaa 1860 agcacaacct cacactcttc agggacgagg acccataagc cgcacacagc cctgagtcaa 1920 tgagcatcca tcctgatggc cacattttct tgggctcact catcttgagg acaaatggga 1980 aaagccagaa gccagagggg cacaaggatg tcacgggata tttcacctgc ctgggatggt 2040 ggaggtagta tggggttttc aatctcaaag cgtccctttc tgccttctcg gctctggcta 2100 tttattccct tgcaccaaca aatacattcg aaaatgttct gtgagctgct caagaaactg 2160 taaaaatgtg tgatgcacgt gcatatgcag agtgggagaa ctttgtgtgt gtgtagaggt 2220 gtgtaggtgt gggtggcatg tgtgcacgcc tgcatgcaat acctgagacc aacctaataa 2280 aggtacaatc ttcatagaac tgcacttgca gcctggagtt gctctggctg aaagtagact 2340 caggcttaag aaatgaaaca taatgcgttt gtctttatag actttaaatt ttcaattatt 2400 actcagttat gtttttggtt taaaaaatta taaaagtcta aaagtaatac atgctcagta 2460 aaaacaagtc cataaaaaat agaagcatat gacaaaaagc ataagtccca caaactccct 2520 agcggtgtgt atgtgtgtgt gtgttattca tggtcacact acatgcaaat taaaaaatga 2580 aagtgtggtc atgctttgtc aactcactat atttttactt tattaactat attctgtatc 2640 agccatctga attgacccaa tctttattgg tgactgcatg aaattccaag gcagggatgt 2700 gtcatatttt ctttagctgg tcccataatc atgaacattt aagtagctcc aatttttcat 2760 caattacaga cattgccgcc atgaacatga ttgcatggcg tgcaagtatt tctgcgaggt 2820 agatttccgt acgggatttc tggggcaaag gg 2852 

1. An isolated polypeptide selected from the group consisting of: a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3-17, and SEQ ID NO:20-31, c) a polypeptide comprising a naturally occurring amino acid sequence at least 92% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:2 and SEQ ID NO:19, d) a polypeptide comprising a naturally occurring amino acid sequence at least 96% identical to the amino acid sequence of SEQ ID NO:18, e) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and f) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-31.
 2. An isolated polypeptide of claim 1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31.
 3. An isolated polynucleotide encoding a polypeptide of claim
 1. 4. An isolated polynucleotide encoding a polypeptide of claim
 2. 5. An isolated polynucleotide of claim 4 comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62.
 6. A recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide of claim
 3. 7. A cell transformed with a recombinant polynucleotide of claim
 6. 8. (CANCELED).
 9. A method of producing a polypeptide of claim 1, the method comprising: a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide, and said recombinant polynucleotide comprises a promoter sequence operably linked to a polynucleotide encoding the polypeptide of claim 1, and b) recovering the polypeptide so expressed.
 10. A method of claim 9, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-31.
 11. An isolated antibody which specifically binds to a polypeptide of claim
 1. 12. An isolated polynucleotide selected from the group consisting of: a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:32-62, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:32 and SEQ ID NO:34-62, c) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 94% identical to the polynucleotide sequence of SEQ ID NO:33, d) a polynucleotide complementary to a polynucleotide of a), e) a polynucleotide complementary to a polynucleotide of b), f) a polynucleotide complementary to a polynucleotide of c), and g) an RNA equivalent of a)-f).
 13. (CANCELED).
 14. A method of detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 12, the method comprising: a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex, and, optionally, if present, the amount thereof.
 15. (CANCELED).
 16. A method of detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 12, the method comprising: a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof, and, optionally, if present, the amount thereof.
 17. A composition comprising a polypeptide of claim 1 and a pharmaceutically acceptable excipient.
 18. A composition of claim 17, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-31.
 19. (CANCELED).
 20. A method of screening a compound for effectiveness as an agonist of a polypeptide of claim 1, the method comprising: a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting agonist activity in the sample.
 21. (CANCELED).
 22. (CANCELED).
 23. A method of screening a compound for effectiveness as an antagonist of a polypeptide of claim 1, the method comprising: a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting antagonist activity in the sample.
 24. (CANCELED).
 25. (CANCELED).
 26. A method of screening for a compound that specifically binds to the polypeptide of claim 1, the method comprising: a) combining the polypeptide of claim 1 with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide of claim 1 to the test compound, thereby identifying a compound that specifically binds to the polypeptide of claim
 1. 27. (CANCELED).
 28. A method of screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a sequence of claim 5, the method comprising: a) exposing a sample comprising the target polynucleotide to a compound, under conditions suitable for the expression of the target polynucleotide, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound.
 29. A method of assessing toxicity of a test compound, the method comprising: a) treating a biological sample containing nucleic acids with the test compound, b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide of claim 12 under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide comprising a polynucleotide sequence of a polynucleotide of claim 12 or fragment thereof, c) quantifying the amount of hybridization complex, and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound. 30-117. (CANCELED). 